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Published: 14 September 2021
Abstract:
Marine sponges often form symbiotic relationships with bacteria that fulfil a specific need within the sponge holobiont, and these symbionts are often conserved within a narrow range of related taxa. To date, there exist only three known bacterial taxa ( Entoporibacteria , SAUL , and Tethybacterales ) that are globally distributed and found in a broad range of sponge hosts, and little is known about the latter two.
, Kehau A. Hagiwara, Ken Liu, Maryam Goudarzi, Wimal Pathmasiri, ,
Published: 14 September 2021
Abstract:
Metabolites from the microbiome influence human, animal, and environmental health, but the diversity and functional roles of these compounds have only begun to be elucidated. Comprehensively characterizing these molecules are significant challenges, as it requires expertise in analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy, skills that not many traditional microbiologists or microbial ecologists possess.
Kailun Zhang, Kiara Pankratz, Hau Duong, Matthew Theodore, Jingwen Guan, Anxiao (Andrew) Jiang, Yiruo Lin,
Published: 14 September 2021
Abstract:
Phage P1 has been shown potentially to play an important role in disseminating antibiotic resistance among bacteria during lysogenization, as evidenced by the prevalence of P1 phage-like elements in animal and human pathogens. In contrast to phage λ, a cell fate decision-making paradigm, P1 lysogenization was shown to be independent of MOI.
Pubo Chen, Jie Huang, Liuyu Rao, Wengen Zhu, Yuhe Yu, Fanshu Xiao, Xiaojuan Chen, Huang Yu, Yongjie Wu, Kui Xu, et al.
Published: 14 September 2021
Abstract:
Understanding the ecological mechanisms governing the resistance and resilience of microbial communities is a key issue to predict their responses to environmental disturbances. Using the zebrafish model, we wanted to clarify the potential mechanisms governing the resistance and resilience of gut microbiota after exposure to silver nanoparticles (AgNPs).
Carter Hoffman, Nazema Y. Siddiqui, Ian Fields, W. Thomas Gregory, Holly M. Simon, Michael A. Mooney, ,
Published: 14 September 2021
Abstract:
Accurate species-level identification from culture-independent techniques is of importance for microbial niches that are less well characterized, such as that of the bladder. 16S rRNA amplicon sequencing, a common culture-independent way to identify bacteria, is often critiqued for lacking species-level resolution. Here, we extensively evaluate classification schemes for species-level bacterial annotation of 16S amplicon data from bladder bacteria.
Fernando Villalón-Letelier, Andrew G. Brooks, ,
Published: 14 September 2021
Abstract:
The antiviral activity of MARCH8 has been associated with the downregulation of envelope glycoproteins from a range of different viruses, resulting in reduced incorporation into nascent virions. Here, we show that MARCH8 restricts IAV at a late stage in virus replication, but this was not associated with reduced expression of IAV envelope glycoproteins on the surfaces of infected cells, pointing to a distinct mechanism of antiviral activity.
Leigh M. Matano, Michael J. Coyne, Leonor García-Bayona, Laurie E. Comstock
Published: 14 September 2021
Abstract:
The bacteroidetocins are a newly discovered class of bacteriocins specific to Bacteroidetes with a spectrum of targets extending from symbiotic gut Bacteroides , Parabacteroides , and Prevotella species to pathogenic oral and vaginal Prevotella species. We previously showed that one such bacteroidetocin, Bd-A, is active at nanomolar concentrations, is water soluble, and is bactericidal, all desirable features in a therapeutic antibacterial peptide.
Wen Su, Sin Fun Sia, Aaron J. Schmitz, Traci L. Bricker, Tyler N. Starr, Allison J. Greaney, Jackson S. Turner, Bassem M. Mohammed, Zhuoming Liu, Ka Tim Choy, et al.
Published: 14 September 2021
Abstract:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs).
Tong Liu, Xi Long, Jia-Peng Zhou, Dong-Wei Tian, Yun-He Yang, Cheng-Gang Zou, , Ming-He Mo, Ke-Qin Zhang
Published: 14 September 2021
Abstract:
Soil fungistasis is a phenomenon in which the germination and growth of fungal propagules is widely inhibited in soil. Although fungistatic compounds are known to play important roles in the formation of soil fungistasis, how such compounds act on soil fungi remains little studied.
, Ana-Belen Martin-Cuadrado, Alfonso Ángel Ramos-Esplá,
Published: 14 September 2021
Abstract:
Posidonia oceanica is a long-living and very slow-growing marine seagrass endemic to the Mediterranean Sea that forms large amounts of leaf material and rhizomes, which can reach the shore and build important banks known as “banquettes.” These banquettes accumulate on the shore, where they can prevent erosion, although they also cause social concern due to their impact on beach use. Furthermore, Posidonia dry material has been considered a source of traditional remedies in several areas of the Mediterranean, and a few studies have been carried out to explore pharmacological activities of Posidonia extracts.
Karen Ross, , Erik Snesrud, Hongzhan Huang, , Jian Zhang, , ,
Published: 14 September 2021
Abstract:
The ability of bacteria to undergo rapid evolution and adapt to changing environmental circumstances drives the public health crisis of multiple antibiotic resistance, as well as outbreaks of disease in economically important agricultural crops and animal husbandry. Prokaryotic transposable elements (TE) play a critical role in this.
Bryan Ho, Daniel Ryback, Basilin Benson, Cayla N. Mason, Pedro J. Torres, Robert A. Quinn, Varykina G. Thackray,
Published: 14 September 2021
Abstract:
Using a combination of untargeted metabolomics and metagenomics, we performed a comparative longitudinal analysis of the feces collected in a cohousing study with a PCOS-like mouse model. Our results showed that gut metabolite composition experienced earlier and more pronounced differentiation in both the disease model and cohoused mice compared with the microbial composition.
Mingi Kim, Do Young Kim, Woon Young Song, So Eun Park, Simone A. Harrison, Walter J. Chazin, Man Hwan Oh,
Published: 14 September 2021
Abstract:
Acinetobacter baumannii has acquired antibiotic resistance at an alarming rate, and it is becoming a serious threat to society, particularly due to the paucity of effective treatment options. Acinetobactin is a siderophore of Acinetobacter baumannii , responsible for active iron supply, and it serves as a key virulence factor to counter host nutritional immunity during infection.
Anuj Tripathi, Ujjal K. Singha, Ayorinde Cooley, Taneisha Gillyard, Evan Krystofiak, Siddharth Pratap, Jamaine Davis,
Published: 14 September 2021
Abstract:
African trypanosomiasis is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei . During its digenetic life cycle, T. brucei undergoes multiple developmental changes to adapt in different environments. T. brucei BF parasites, dwelling in mammalian blood, produce ATP from glycolysis and hydrolyze ATP in mitochondria for generation of inner membrane potential.
Chih-Feng Wu, , , Lin Chou, Surtaz Khan, , ,
Published: 14 September 2021
Abstract:
The T6SS is used by several taxa of Gram-negative bacteria to secrete toxic effector proteins to attack others. Diversification of effector collections shapes bacterial interactions and impacts the health of hosts and ecosystems in which bacteria reside.
Samane Rahmdel,
Published: 14 September 2021
Abstract:
The stratum corneum is the outermost layer of the epidermis and is thus directly exposed to the environment. It consists mainly of corneocytes, which are keratinocytes in the last stage of differentiation, having neither nuclei nor organelles.
Marina Dziuba, Cornelius N. Riese, Lion Borgert, Manuel Wittchen, Tobias Busche, , ,
Published: 14 September 2021
Abstract:
Magnetosomes have emerged as a model system to study prokaryotic organelles and a source of biocompatible magnetic nanoparticles for various biomedical applications. However, the lack of knowledge about the transcriptional organization of magnetosome gene clusters has severely impeded the engineering, manipulation, and transfer of this highly complex biosynthetic pathway into other organisms.
, Albert Rivas Ubach, Anil K. Battu
Published: 14 September 2021
Abstract:
Plant roots and the associated rhizosphere constitute a dynamic environment that fosters numerous intra- and interkingdom interactions, including metabolite exchange between plants and soil mediated by root exudates and the rhizosphere microbiome. These interactions affect plant fitness and performance, soil health, and the belowground carbon budget.
Merve Cakir, Kirsten Obernier, Antoine Forget, Nevan J. Krogan
Published: 14 September 2021
Abstract:
Current epidemics, such as HIV or influenza, and the emergence of new threatening pathogens, such as the one causing the current coronavirus disease 2019 (COVID-19) pandemic, represent major global health challenges. While vaccination is an important part of the arsenal to counter the spread of viral diseases, it presents limitations and needs to be complemented by efficient therapeutic solutions.
, , , , Katherine R. Murphy, Chao Qi, Egon A. Ozer,
Published: 14 September 2021
Abstract:
Klebsiella pneumoniae can cause severe infections in the blood, urinary tract, and lungs. Resistance to carbapenems in K. pneumoniae is an urgent public health threat, since it can make these isolates difficult to treat.
Marion Leclerc, Cassandre Bedu-Ferrari, Lucie Etienne-Mesmin, Mahendra Mariadassou, Lucie Lebreuilly, Seav-Ly Tran, Laurence Brazeau, Camille Mayeur, Julien Delmas, Olivier Rué, et al.
Published: 14 September 2021
Abstract:
Gut microbiota dysbiosis has been associated with inflammatory diseases. The human inflammatory response leads to an overproduction of nitric oxide (NO) in the gut.
Christopher N. Vassallo, Govind Prasad Sah, Michael L. Weltzer,
Published: 14 September 2021
Abstract:
Many bacterial species use diverse systems to deliver bacteriocins or toxins to neighboring competing cells. These systems are often selective in targeting cells that are related to themselves and therefore compete in the same niches for resources.
Anil Pant, Lara Dsouza,
Published: 14 September 2021
Abstract:
Cellular activities are finely regulated by numerous signaling pathways to support specific functions of complex life processes. Viruses are obligate intracellular parasites.
Li Wang, Isabel Sola, , Sonia Zuñiga
Published: 14 September 2021
Abstract:
Coronaviruses (CoVs) are emerging pathogens causing life-threatening diseases in humans. Knowledge of virus-host interactions and viral subversion mechanisms of host pathways is required for the development of effective countermeasures against CoVs.
, , , Michael D. Kubo, Tori M. Hoehler, , Dawn Cardace,
Published: 14 September 2021
Abstract:
Microbial communities existing under extreme or stressful conditions have long been thought to be structured primarily by deterministic processes. The application of macroecology theory and modeling to microbial communities in recent years has spurred assessment of assembly processes in microbial communities, revealing that both stochastic and deterministic processes are at play to different extents within natural environments.
Silke Rath, Katharina Rox, Sven Kleine Bardenhorst, Ulf Schminke, Marcus Dörr, Julia Mayerle, Fabian Frost, Markus M. Lerch, André Karch, , et al.
Published: 14 September 2021
Abstract:
Many cohort studies have investigated the link between diet and plasma TMAO levels, reporting incongruent results, while gut microbiota were only recently included into analyses. In these studies, taxonomic data were recorded that are not a good proxy for TMA formation, as specific members of various taxa exhibit genes catalyzing this reaction, demanding function-based technologies for accurate quantification of TMA-synthesizing bacteria.
Marlene K. Wolfe, Aaron Topol, Alisha Knudson, Adrian Simpson, Bradley White, Duc J. Vugia, Alexander T. Yu, Linlin Li, Michael Balliet, Pamela Stoddard, et al.
Published: 14 September 2021
Abstract:
Access to reliable, rapid monitoring data is critical to guide response to an infectious disease outbreak. For pathogens that are shed in feces or urine, monitoring wastewater can provide a cost-effective snapshot of transmission in an entire community via a single sample.
Christian Diener, Shizhen Qin, Yong Zhou, Sushmita Patwardhan, Li Tang, Jennifer C. Lovejoy, Andrew T. Magis, Nathan D. Price, Leroy Hood,
Published: 14 September 2021
Abstract:
Recent human feeding studies have shown how the baseline taxonomic composition of the gut microbiome can determine responses to dietary interventions, but the exact functional determinants underlying this phenomenon remain unclear. In this study, we set out to better understand interactions between baseline BMI, metabolic health, diet, gut microbiome functional profiles, and subsequent weight changes in a human cohort that underwent a healthy lifestyle intervention.
Zheng Qu, Hongxiang Zhang, Qianqian Wang, Huizhang Zhao, Xiaofan Liu, Yanping Fu, Yang Lin, Jiatao Xie, Jiasen Cheng, Bo Li, et al.
Published: 14 September 2021
Abstract:
Although endophytes are widespread in nature, the interactions between endophytes and their hosts are still not fully understood. Members of a unique class of endophytes, the virus-mediated endophytic fungi, are continuously being discovered and have received wide attention. In this study, we investigated the interaction between a mycovirus-mediated endophytic fungus and its host rapeseed by using dual-UMI RNA-seq.
Anna Olsson, Marcus Hong, Hissa Al-Farsi, Christian G. Giske, Pernilla Lagerbäck,
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01065-21

Abstract:
Objectives. Carbapenemase-producing Enterobacterales pose an increasing medical threat. Combination therapy is often used for severe infections; however, there is little evidence supporting the optimal selection of drugs. This study aimed to determine the in vitro effects of polymyxin B combinations against carbapenemase-producing Escherichia coli . Methods. The interactions of polymyxin B in combination with aztreonam, meropenem, minocycline or rifampicin against 20 clinical isolates of NDM and OXA-48-group-producing E. coli were evaluated using time-lapse microscopy. 24-h samples were spotted on plates with and without 4 x MIC polymyxin B for viable counts. Whole-genome sequencing was applied to identify resistance genes and mutations. Finally, potential associations between combination effects and bacterial genotypes were assessed using Fisher’s exact test. Results. Synergistic and bactericidal effects were observed with polymyxin B and minocycline against 11/20 strains and with polymyxin B and rifampicin against 9/20 strains. The combinations of polymyxin B and aztreonam or meropenem showed synergy against 2/20 strains. Negligible resistance development against polymyxin B was detected. Synergy with polymyxin B and minocycline was associated with genes involved in efflux (presence of tet(B) , wildtype soxR and the marB mutation H44Q) and lipopolysaccharide synthesis ( eptA C27Y, lpxB mutations and lpxK L323S). Synergy with polymyxin B and rifampicin was associated with sequence variations in arnT , which plays a role in lipid A modification. Conclusion. Polymyxin B in combination with minocycline or rifampicin frequently showed positive interactions against NDM- and OXA-48-group-producing E. coli . Synergy was associated with genes encoding efflux and components of the bacterial outer membrane.
Junya De Lacorte Singulani, Lariane Teodoro Oliveira, Marina Dorisse Ramos, Nathália Ferreira Fregonezi, Paulo César Gomes, Mariana Cristina Galeane, Mario Sergio Palma, Ana Marisa Fusco Almeida, Maria José Soares Mendes Giannini
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.00904-21

Abstract:
Cryptococcosis is associated with high rates of morbidity and mortality, especially in AIDS patients. Its treatment is carried out by combining amphotericin B and azoles or flucytosine, which cause unavoidable toxicity issues to the host. Thus, the urgency in obtaining new antifungals drives the search for antimicrobial peptides (AMPs). This study aimed to extend the understanding of the mechanism of action of an AMP analog from wasps peptide toxins, MK58911-NH2, on Cryptococcus neoformans . It was also evaluated if MK58911-NH2 can act on cryptococcal cells in macrophages, biofilms, and an immersion zebrafish model of infection. Finally, we investigated the structure-antifungal action and the toxicity relation of MK58911-NH2 fragments and a derivative of this peptide (MH58911-NH2). The results demonstrated that MK58911-NH2 did not alter the fluorescence intensity of cell wall - binding dye calcofluor or capsule- binding dye 18b7 antibody-FITC of C. neoformans , but rather reduced the number and size of fungal cells. This activity reduced the fungal burden of C. neoformans both in macrophages and in zebrafish embryos as well as within biofilms. Three fragments of the MK58911-NH2 peptide showed no activity against Cryptococcus or toxicity in lung cells. The derivative peptide MH58911-NH2, in which the lysine residues of MK58911-NH2 were replaced by histidine, reduced the activity against extracellular and intracellular C. neoformans . On the other hand, it was active against biofilm, and reducing toxicity. In summary, the results showed that peptide MK58911-NH2 could be a promising agent against cryptococcosis. The work also opens a perspective for the verification of the antifungal activity of other derivatives.
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01596-21

Abstract:
We performed whole genome sequencing for 17 Enterobacter clinical strains and analyzed all available Enterobacter genomes and its closely-related genera (n=3,389) from NCBI. The exact origin of plasmid-borne bla CMH and bla MIR genes is Enterobacter cloacae and Enterobacter roggenkampii , respectively, while plasmid-borne bla ACT genes originated from multiple other Enterobacter species including Enterobacter xiangfangensis , Enterobacter hoffmannii , and Enterobacter asburiae , Enterobacter ludwigii , and Enterobacter kobei . The genus of Enterobacter represents a large reservoir of plasmid-borne AmpC β-lactamase.
Elizabeth L. Castle, Carolyn-Ann Robinson, Pauline Douglas, Kristina D. Rinker,
Molecular and Cellular Biology; https://doi.org/10.1128/mcb.00399-21

Abstract:
Processing bodies (PBs) are ribonucleoprotein granules important for cytokine mRNA decay that are targeted for disassembly by many viruses. Kaposi’s sarcoma-associated herpesvirus is the etiological agent of the inflammatory endothelial cancer, Kaposi’s sarcoma, and a PB-regulating virus. The virus encodes Kaposin B (KapB), which induces actin stress fibres (SFs) and cell spindling as well as PB disassembly. We now show that KapB-mediated PB disassembly requires actin rearrangements, RhoA effectors and the mechanoresponsive transcription activator, YAP. Moreover, ectopic expression of active YAP or exposure of ECs to mechanical forces caused PB disassembly in the absence of KapB. We propose that the viral protein KapB activates a mechanoresponsive signaling axis and links changes in cell shape and cytoskeletal structures to enhanced inflammatory molecule expression using PB disassembly. Our work implies that cytoskeletal changes in other pathologies may similarly impact the inflammatory environment.
Journal of Bacteriology; https://doi.org/10.1128/jb.00344-21

Abstract:
Small membrane proteins represent a subset of recently discovered small proteins (≤100 amino acids), which are a ubiquitous class of emerging regulators underlying bacterial adaptation to environmental stressors. Until relatively recently, small open reading frames encoding these proteins were not designated as genes in genome annotations. Therefore, our understanding of small protein biology was primarily limited to a few candidates associated with previously characterized larger partner proteins. Following the first systematic analyses of small proteins in E. coli over a decade ago, numerous small proteins have been uncovered across different bacteria. An estimated one-third of these newly discovered proteins are localized to the cell membrane, where they may interact with distinct groups of membrane proteins such as signal receptors, transporters, and enzymes, and affect their activities. Recently, there has been considerable progress in functionally characterizing small membrane protein regulators aided by innovative tools adapted specifically to study small proteins. Our review covers prototypical proteins that modulate a broad range of cellular processes such as transport, signal transduction, stress response, respiration, cell division, sporulation as well as membrane stability. Thus, small membrane proteins represent a versatile group of regulators of physiology not just at the membrane but the whole cell. Additionally, small membrane proteins have the potential for clinical applications, where some of the proteins may act as antibacterial agents themselves, while others serve as alternative drug targets for the development of novel antimicrobials.
Ranjit Chauhan, Qilan Li, Molly E. Woodson, Makafui Gasonoo, Marvin J. Meyers,
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01460-21

Abstract:
The Hepatitis B Virus (HBV) ribonuclease H (RNase H) is an attractive but unexploited drug target. Here, we addressed three limitations to the current state of RNase H inhibitor development: i) Efficacy has been assessed only in transfected cell lines; ii) Cytotoxicity data are from transformed cell lines rather than primary cells; and iii) It is unknown how the compounds work against nucleos(t)ide analog resistant HBV strains. Three RNase H inhibitors from different chemotypes, 110 (α-hydroxytropolone), 1133 (N-hydroxypyridinedione), and 1073 (N-hydroxynapthyridinone), were tested in HBV-infected HepG2-NTCP cells for inhibition of cccDNA accumulation and HBV product formation. 50% effective concentrations (EC 50 s) were 0.049-0.078 μM in the infection studies compared to 0.29-1.6 μM in transfected cells. All compounds suppressed cccDNA formation by >98% at 5 μM when added shortly after infection. HBV RNA, intracellular and extracellular DNA, and HBsAg secretion were all robustly suppressed. The greater efficacy of the inhibitors when added shortly after infection is presumably due to blocking amplification of the HBV cccDNA, which suppresses events downstream of cccDNA formation. The compounds had 50% cytotoxic concentrations (CC 50 s) of 16-100 μM in HepG2-derived cell lines but were non-toxic in primary human hepatocytes, possibly due to the quiescent state of the hepatocytes. The compounds had similar EC 50 s against replication of wild-type, Lamivudine-resistant and Adefovir/Lamivudine-resistant HBV, as expected because the RNase H inhibitors do not target the viral reverse transcriptase active site. These studies expand confidence in inhibiting the HBV RNase H as a drug strategy and support inclusion of RNase H inhibitors in novel curative drug combinations for HBV.
Jesse M. Hall, Graham J. Bitzer, Megan A. DeJong, Jason Kang, Ting Y. Wong, M. Allison Wolf, Justin R Bevere, ,
Infection and Immunity; https://doi.org/10.1128/iai.00346-21

Abstract:
Pertussis is a respiratory disease caused by the Gram-negative pathogen, Bordetella pertussis ( Bp ). The transition from a whole cell pertussis vaccine (wP; DTP) to an acellular pertussis vaccine (aP; DTaP; Tdap) correlates with an increase in pertussis cases, despite widespread vaccine implementation and coverage, and it is now appreciated that the protection provided by aP rapidly wanes. To recapitulate the localized immunity observed from natural infection, mucosal vaccination with aP was explored using the coughing rat model of pertussis. Overall, our goal was to evaluate the route of vaccination in the coughing rat model of pertussis. Immunity induced by both oral gavage (OG) and intranasal (IN) vaccination of aP in Bp challenged rats over a nine-day infection was compared to intramuscular (IM)-wP and IM-aP immunized rats that were used as positive controls. Our data demonstrate that mucosal immunization of aP resulted in production of anti- Bp IgG antibody titers similar to IM-wP and IM-aP vaccinated controls post-challenge. IN-aP also induced anti- Bp IgA antibodies in the nasal cavity. Immunization with IM-wP, IM-aP, IN-aP, and OG-aP immunization protected against Bp induced cough, while OG-aP immunization did not protect against respiratory distress. Mucosal immunization by both IN and OG administration protected against acute inflammation and decreased bacterial burden in the lung compared to mock vaccinated challenge (MVC) rats. The data presented in this study suggests that mucosal vaccination with aP can induce a mucosal immune response and provide protection against Bp challenge. This study highlights the potential benefits and uses of the coughing rat model of pertussis; however, further questions regarding waning immunity still require additional investigation.
Olumide Martins, Jin Lee, , Nicole C. Ammerman, , Eric L. Nuermberger
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01545-21

Abstract:
Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multi-drug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy, toxic, and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus , where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.
M. I. Islam, J. H. Bae, T Ishida, P Ridone, J Lin, M. J. Kelso, Y Sowa, B. J. Buckley,
Journal of Bacteriology; https://doi.org/10.1128/jb.00367-21

Abstract:
The bacterial flagellar motor (BFM) is a protein complex that confers motility to cells and contributes to survival and virulence. The BFM consists of stators that are ion-selective membrane protein complexes and a rotor that directly connects to a large filament, acting as a propeller. The stator complexes couple ion transit across the membrane to torque that drives rotation of the motor. The most common ion gradients that drive BFM rotation are protons (H + ) and sodium ions (Na + ). The sodium-powered stators, like those in the PomAPomB stator complex of Vibrio spp, can be inhibited by sodium channel inhibitors, in particular, by phenamil, a potent and widely used inhibitor. However, relatively few new sodium-motility inhibitors have been described since the discovery of phenamil. In this study, we characterised two possible motility inhibitors HM2-16F and BB2-50F from a small library of previously reported amiloride derivatives. We used three approaches: effect on rotation of tethered cells, effect on free swimming bacteria and effect on rotation of marker beads. We showed that both HM2-16F and BB2-50F stopped rotation of tethered cells driven by Na + motors comparable to phenamil at matching concentrations, and could also stop rotation of tethered cells driven by H + motors. Bead measurements in presence and absence of stators confirmed that the compounds did not inhibit rotation via direct association with the stator, in contrast to the established mode of action of phenamil. Overall, HM2-16F and BB2-50F stopped swimming in both Na + and H + stator types, and in pathogenic and non-pathogenic strains. Importance: Here we characterised two novel amiloride derivatives in the search for antimicrobial compounds that target bacterial motility. Our two compounds were shown to inhibit flagellar motility at 10 μM across multiple strains, from non-pathogenic E. coli with flagellar rotation driven by proton or chimeric sodium-powered stators, to proton-powered pathogenic E. coli (EHEC/UPEC) and lastly in sodium-powered Vibrio alginolyticus . Broad anti-motility compounds such as these are important tools in our efforts control virulence of pathogens in health and agricultural settings.
Aleksandra Tymoszewska, , , Małgorzata SŁodownik, Edyta Maron, Beatriz Martínez,
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.00921-21

Abstract:
Resistance to non-ribosomally synthesized peptide antibiotics affecting the cell envelope is well-studied and mostly associated with the action of peptide-sensing and detoxification (PSD) modules which consist of a two-component system (TCS) and an ATP-binding cassette (ABC) transporter. In contrast, the resistance mechanisms to ribosomally synthesized bacterial toxic peptides (bacteriocins), which also affect the cell envelope, are studied to lesser extent, and possible cross-resistance between them and antibiotics is still poorly understood. In the present study, we investigated the development of resistance of Lactococcus lactis to aureocin A53- and enterocin L50-like bacteriocins and cross-resistance with antibiotics. First, 19 spontaneous mutants resistant to their representatives were selected and displayed changes in the sensitivity also to peptide antibiotics acting on the cell envelope (bacitracin, daptomycin, and gramicidin). Sequencing of their genomes revealed mutations in genes encoding ABC transporter YsaCB and TCS KinG-LlrG, the emergence of which induced upregulation of the dltABCD and ysaDCB operons. The ysaB mutations were either nonsense or frameshift and led to the generation of truncated YsaB but with the conserved N-terminal FtsX domain intact. Deletions of ysaCB or llrG had a minor effect on the resistance of the obtained mutants to the tested bacteriocins, daptomycin, and gramicidin, indicating that the development of resistance is dependent on the modification of the protein rather than its absence. In further corroboration of the above conclusion, we show that the FtsX domain, which functions effectively when the YsaB is lacking its central and C-terminal parts, is critical for the resistance to these antimicrobials.
Corelle A. Z. Rokicki, James R. Brenner, Alexander H. Dills, Julius J. Judd, Jemila C. Kester, Julia Puffal, Ian L. Sparks, Malavika Prithviraj, Brittany R. Anderson, , et al.
Journal of Bacteriology; https://doi.org/10.1128/jb.00419-21

Abstract:
Mycobacteria spatially organize their plasma membrane, and many enzymes involved in envelope biosynthesis associate with a membrane compartment termed the intracellular membrane domain (IMD). The IMD is concentrated in the polar regions of growing cells and becomes less polarized under non-growing conditions. Because mycobacteria elongate from the poles, the observed polar localization of the IMD during growth likely supports the localized biosynthesis of envelope components. While we have identified more than 300 IMD-associated proteins by proteomic analyses, only a handful of these have been verified by independent experimental methods. Furthermore, some IMD-associated proteins may have escaped proteomic identification and remain to be identified. Here, we visually screened an arrayed library of 523 Mycobacterium smegmatis strains, each producing a Dendra2-FLAG-tagged recombinant protein. We identified 29 fusion proteins that showed polar fluorescence patterns characteristic of IMD proteins. Twenty of these had previously been suggested to localize to the IMD based on proteomic data. Of the nine remaining IMD candidate proteins, three were confirmed by biochemical methods to be associated with the IMD. Taken together, this new co-localization strategy is effective in verifying the IMD association of proteins found by proteomic analyses, while facilitating the discovery of additional IMD-associated proteins. Importance The intracellular membrane domain (IMD) is a membrane subcompartment found in Mycobacterium smegmatis cells. Proteomic analysis of purified IMD identified more than 300 proteins, including enzymes involved in cell envelope biosynthesis. However, proteomics on its own is unlikely to detect every IMD-associated protein because of technical and biological limitations. Here, we describe fluorescent protein co-localization as an alternative, independent approach. Using a combination of fluorescence microscopy, proteomics, and subcellular fractionation, we identified three new proteins associated with the IMD. Such a robust method to rigorously define IMD proteins will benefit future investigations to decipher the synthesis, maintenance and functions of this membrane domain, and help delineate a more general mechanisms of subcellular protein localization in mycobacteria.
Mallika Imwong, Kanokon Suwannasin, Suttipat Srisutham, Ranitha Vongpromek, Cholrawee Promnarate, Aungkana Saejeng, , Stephane Proux, Tiengkham Pongvongsa, Chea Nguon, et al.
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01121-21

Abstract:
Increasing drug resistance in Plasmodium falciparum to artemisinins and their ACT partner drugs jeopardises effective antimalarial treatment. Resistance is worst in the Greater Mekong Subregion. Monitoring genetic markers of resistance can help to guide antimalarial therapy. Markers of resistance to artemisinins ( PfKelch mutations), mefloquine (amplification of P. falciparum multidrug resistance-1, PfMDR1, ), and piperaquine ( PfPlasmepsin2/3 amplification and specific P. falciparum chloroquine resistance transporter, PfCRT, mutations) were assessed in 6,722 P. falciparum samples from Vietnam, Lao PDR, Cambodia, Thailand, Myanmar between 2007 and 2019. Against a high background prevalence of PfKelch mutations, PfMDR1 and PfPlasmepsin2/3 amplification closely followed regional drug pressures over time. PfPlasmepsin2/3 amplification preceded piperaquine-resistance associated PfCRT mutations in Cambodia, and reached a peak prevalence of 23/28 (82%) in 2015. This declined to 57/156 (38%) after changing first-line treatment away from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. PfMDR1 amplification increased from 0/293 (0%) between 2012 and 2017 to 12/156 (8%) in 2019. Amplification of PfMDR1 and PfPlasmepsin2/3 in the same parasites was extremely rare (4/6,722; 0.06%) and dispersed over time. Mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy.
Mandong Hu, Zongwei Li, Dingchen Li, Fangyan Chen, Jingya Zhao, Yong Chen, Zelei Wang,
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.00291-21

Abstract:
Aspergillus fumigatus causes a series of invasive diseases, including the high-mortality invasive aspergillosis, and has been a serious global health threat because of its increased resistance to the first-line clinical triazoles. We analyzed the whole-genome sequence of 15 A. fumigatus strains from China and found that long terminal repeat retrotransposons (LTR-RTs), including Afut1 , Afut2, Afut3, and Afut4 , are most common and have the largest total nucleotide length among all transposable elements in A. fumigatus . Deleting one of the most enriched Afut4 977-sac1 in azole-resistant strains decreased azole resistance and downregulated its nearby gene, sac1 , but it did not significantly affect the expression of genes of the ergosterol synthesis pathway. We then discovered that 5'LTR of Afut4 977-sac1 had promoter activity and enhanced the adjacent sac1 gene expression. We found that sac1 is important to A. fumigatus , and the upregulated sac1 caused the elevated resistance of A. fumigatus to azoles. Finally, we showed that Afut4 977-sac1 has an evolution pattern similar to that of the whole genome of azole-resistant strains due to azoles; phylogenetic analysis on both the whole genome and Afut4 977-sac1 suggests that the insertion of Afut4 977-sac1 might have preceded the emergence of azole-resistant strains. Taking these data together, we found that LTR-RT Afut4 977-sac1 might be involved in the regulation of azole resistance of A. fumigatus by upregulating its nearby sac1 gene.
Anastasia Gant Kanegusuku, Isidora N. Stankovic, Pamela A. Cote-Hammarlof, Priscilla H. Yong, Christine A. White-Ziegler
Journal of Bacteriology; https://doi.org/10.1128/jb.00363-21

Abstract:
One of the first environmental cues sensed by a microbe as it enters a human host is an upshift in temperature to 37°C. In this dynamic timepoint analysis, we demonstrate that this environmental transition rapidly signals a multitude of gene expression changes in Escherichia coli . Bacteria grown at 23°C under aerobic conditions were shifted to 37°C and mRNA expression was measured at timepoints after the shift to 37°C (t=0.5, 1, and 4 hours). The first hour is characterized by a transient shift to anaerobic respiration strategies and stress responses, particularly acid resistance, indicating that temperature serves as a sentinel cue to predict and prepare for various niches within the host. The temperature effects on a subset of stress response genes were shown to be mediated by RpoS, directly correlated with RpoS, DsrA and RprA levels, and increased acid resistance was observed that was dependent on 23°C growth and RpoS. By 4 hours, gene expression shifted to aerobic respiration pathways, decreased stress responses, coupled with increases in genes associated with biosynthesis (amino acid, nucleotides), iron uptake, and host defense. ompT , a gene that confers resistance to antimicrobial peptides, was highly thermoregulated and with a pattern conserved in enteropathogenic and uropathogenic E. coli . An immediate decrease in curli gene expression concomitant with an increase in flagellar gene expression implicates temperature in this developmental decision. Together, our studies demonstrate that temperature signals a reprogramming of gene expression immediately upon an upshift that may predict, prepare, and benefit survival of the bacterium within the host. IMPORTANCE: As one of the first cues sensed by the microbe upon entry into a human host, understanding how bacteria like E. coli modulate gene expression in response to temperature improves our understanding of how bacteria immediately initiate responses beneficial to survival and colonization. For pathogens, understanding the various pathways of thermal regulation could yield valuable targets for anti-infective chemotherapeutic drugs or disinfection measures. In addition, our data provide a dynamic examination of the RpoS stress response, providing genome-wide support for how temperature impacts RpoS through changes in RpoS stability and modulation by small regulatory RNAs.
Dan Li, Philip E. Sabato, Benjamin Guiastrennec, Aziz Ouerdani, Hwa-Ping Feng, Vincent Duval, Carisa S. De Anda, Pamela S. Sears, Margaret Z. Chou, Catherine Hardalo, et al.
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.00895-21

Abstract:
Tedizolid phosphate is an oxazolidinone antibacterial agent approved for treatment of gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration–time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the minimum inhibitory concentration susceptibility breakpoint of 0.5 μg/mL for Staphylococcus and Streptococcus was 100%. As most participants from the PN012 trial were cured, no significant exposure–efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar to adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.
Hemendra Pal Singh Dhaked, Luyang Cao,
Journal of Bacteriology; https://doi.org/10.1128/jb.00330-21

Abstract:
Streptococcus mutans , a dental pathogen, encodes the ComDE two-component system comprised of a histidine kinase (ComD) and a response regulator (ComE). This system is necessary for production of bacteriocins and development of genetic competence. ComE interacts with its cognate promoters to activate the transcription of bacteriocin and competence related genes. Previous transcriptomic studies indicated that expressions of bacteriocin genes were upregulated in the presence of oxygen. To understand the relationship between the aerobic condition and bacteriocin expression, we analyzed the S. mutans ComE sequence and its close homologs. Surprisingly, we noticed the presence of cysteine (Cys) residues located at positions 200 and 229, which are highly conserved among the ComE homologs. Here we investigated the role of Cys residues of S. mutans ComE in the activation of bacteriocin transcription using the P nlmA promoter that expresses bacteriocin NlmA. We constructed both single mutants and double mutants by replacing the Cys residues with serine and performed complementation assays. We observed that the presence of Cys residues is essential for P nlmA activation. With purified ComE mutant proteins we found that ComE double mutants displayed a nearly two-fold lower association rate than wild-type ComE. Furthermore, ANS fluorescence studies indicated that the double mutants displayed wider conformation changes than wild-type ComE. Finally, we demonstrated that close streptococcal ComE homologs successfully activate the P nlmA expression in vivo . This is the first report suggesting that S. mutans ComE and its homologs can sense the oxidation status of the cell, a phenomenon similar to the AgrA system of Staphylococcus aureus but with different outcome. IMPORTANCE Streptococci are an important species that prefer to grow under anaerobic or microaerophilic environments. Studies have shown that streptococci growth in an aerobic environment generates oxidative stress responses by activating various defense systems including production of antimicrobial peptides called bacteriocins. This study highlights the importance of a two-component response regulator (ComE) that senses the aerobic environment and induces bacteriocin production in Streptococcus mutans , a dental pathogen. We believe increased bacteriocin secretion under aerobic conditions is necessary for survival and colonization of S. mutans in the oral cavity by inhibiting other competing organisms. Redox sensing by response regulator might be a wide-spread phenomenon, since two other ComE homologs from pathogenic streptococci that inhabit diverse environmental niches also perform a similar function.
Maria E. Cilento, Aaron B. Reeve, Eleftherios Michailidis, Tatiana V. Ilina, Eva Nagy, Hiroaki Mitsuya, Michael A. Parniak, Philip R. Tedbury, Stefan G. Sarafianos
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01167-21

Abstract:
4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA, MK-8591, islatravir) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with exceptional potency against WT and drug-resistant HIV-1, in Phase III clinical trials. EFdA resistance is not well characterized. To study EFdA-resistance patterns as it may emerge in naïve or tenofovir- (TFV), emtricitabine/lamivudine- (FTC/3TC), or zidovudine- (AZT) treated patients we performed viral passaging experiments starting with wild-type, K65R, M184V, or D67N/K70R/T215F/K219Q HIV-1. Regardless the starting viral sequence, all selected EFdA-resistant variants included the M184V RT mutation. Using recombinant viruses, we validated the role for M184V as the primary determinant of EFdA resistance; none of the observed connection subdomain (R358K and E399K) or RNase H domain (A502V) mutations significantly contributed to EFdA resistance. A novel EFdA resistance mutational pattern that included A114S was identified in the background of M184V. A114S/M184V exhibited higher EFdA resistance (∼24-fold) than M184V (∼8-fold) or A114S alone (∼2-fold). Remarkably, A114S/M184V and A114S/M184V/A502V resistance mutations were up to 50-fold more sensitive to tenofovir than WT HIV-1. These mutants also had significantly lower specific infectivity than WT. Biochemical experiments confirmed decreases in the enzymatic efficiency (k cat /K m ) of WT vs. A114S (2.1-fold) and A114S/M184V/A502V (6.5-fold) RTs, with no effect of A502V on enzymatic efficiency or specific infectivity. The rather modest EFdA resistance of M184V or A114S/M184V (8- and 24-fold), their hypersusceptibility to tenofovir, and strong published in vitro and in vivo data, suggest that EFdA is an excellent therapeutic candidate for naïve, AZT-, FTC/3TC, and especially tenofovir-treated patients.
Eon-Min Ko, Ju-Yeon Kim, Sujin Lee, Suhkmann Kim, Jihwan Hwang,
Journal of Bacteriology; https://doi.org/10.1128/jb.00402-21

Abstract:
Mycobacterium smegmatis has two isocitrate lyase (ICL) isozymes (MSMEG_0911 and MSMEG_3706). We demonstrated that ICL1 (MSMEG_0911) is the predominantly expressed ICL in M. smegmatis and plays a major role in growth on acetate or fatty acid as the sole carbon and energy source. Expression of the icl1 gene in M. smegmatis was demonstrated to be strongly upregulated during growth on acetate relative to that in M. smegmatis grown on glucose. Expression of icl1 was shown to be positively regulated by the RamB activator, and three RamB-binding sites (RamBS1, RamBS2, and RamBS3) were identified in the upstream region of icl1 using DNase I footprinting analysis. Succinyl-CoA was shown to increase the binding affinity of RamB to its binding sites and enable RamB to bind to RamBS2 that is the most important site for RamB-mediated induction of icl1 expression. These results suggest that succinyl-CoA serves as a coinducer molecule for RamB. Our study also showed that cAMP receptor protein (Crp1: MSMEG_6189) represses icl1 expression in M. smegmatis grown in the presence of glucose. Therefore, the strong induction of icl1 expression during growth on acetate as the sole carbon source relative to the weak expression of icl1 during growth on glucose is likely to result from combined effects of RamB-mediated induction of icl1 in the presence of acetate and Crp-mediated repression of icl1 in the presence of glucose. IMPORTANCE Carbon flux through the glyoxylate shunt has been suggested to affect virulence, persistence, and antibiotic resistance of Mycobacterium tuberculosis . Therefore, it is important to understand the precise mechanism underlying the regulation of the icl gene encoding the key enzyme of the glyoxylate shunt. Using Mycobacterium smegmatis , this study revealed the regulation mechanism underlying induction of icl1 expression in M. smegmatis when the glyoxylate shunt is required. The conservation of the cis - and trans -acting regulatory elements related to icl1 regulation in both M. smegmatis and M. tuberculosis implies that the similar regulatory mechanism operates for the regulation of icl1 expression in M. tuberculosis .
Swetha Kassety, Stefan Katharios-Lanwermeyer, George A. O’Toole,
Journal of Bacteriology; https://doi.org/10.1128/jb.00265-21

Abstract:
Pseudomonas aeruginosa strains PA14 and PAO1 are among the two best characterized model organisms used to study the mechanisms of biofilm formation, while also representing two distinct lineages of P. aeruginosa . Previous work has shown that PA14 and PAO1 use different strategies for surface colonization; they also have different extracellular matrix composition and different propensities to disperse from biofilms back into the planktonic phase surrounding them. We expand on this work here by exploring the consequences of these different biofilm production strategies during direct competition. Using differentially labeled strains and microfluidic culture methods, we show that PAO1 can outcompete PA14 in direct competition during early colonization and subsequent biofilm growth, that they can do so in constant and perturbed environments, and that this advantage is specific to biofilm growth and requires production of the Psl polysaccharide. In contrast, the P. aeruginosa PA14 is better able to invade pre-formed biofilms and is more inclined to remain surface-associated under starvation conditions. These data together suggest that while P. aeruginosa PAO1 and PA14 are both able to effectively colonize surfaces, they do so in different ways that are advantageous under different environmental settings. Importance Recent studies indicate that P. aeruginosa PAO1 and PA14 use distinct strategies to initiate biofilm formation. We investigated whether their respective colonization and matrix secretion strategies impact their ability to compete under different biofilm-forming regimes. Our work shows that these different strategies do indeed impact how these strains fair in direct competition: PAO1 dominates during colonization of a naïve surface, while PA14 is more effective in colonizing a pre-formed biofilm. These data suggest that even for very similar microbes there can be distinct strategies to successfully colonize and persist on surfaces during the biofilm life cycle.
Sydney L. Drury, Anderson R. Miller, Clare L. Laut, Alec B. Walter, Monique R. Bennett, Meng Su, Mingfeng Bai, Bingwen Jing, Scott B Joseph, Edward J. Metzger, et al.
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.00919-21

Abstract:
Staphylococcus aureus is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant S. aureus is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are underway to develop therapies that target essential biological processes in S. aureus . Antimicrobial photodynamic therapy is effective alternative to antibiotics, therefore we developed an approach to simultaneously expose S. aureus to intracellular and extracellular photoactivators. A near infrared photosensitizer was conjugated to human monoclonal antibodies (mAbs) that target the S. aureus Isd heme acquisition proteins. Additionally, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial PDT treatment of drug-resistant S. aureus exposed to VU0038882 and conjugated anti-Isd mAbs proved to be an effective antibacterial strategy in vitro and in a murine model of SSTIs.
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