Antimicrobial Agents and Chemotherapy

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ISSN / EISSN : 0066-4804 / 1098-6596
Published by: American Society for Microbiology (10.1128)
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Junqi Liu, Gang Xiao, Wangping Zhou, Jun Yang,
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01503-21

Abstract:
Inhibition of vital respiratory enzymes, such as NADH: ubiquinone oxidoreductase (complex I), type II NADH-quinone oxidoreductases (NDH-2), and malate: quinone oxidoreductase, in the inner membrane, is a secondary antibacterial mechanism of colistin (1–3). However, colistin resistance mechanisms associated with this secondary mode of action of colistin have rarely been reported. Herein, we confirmed that the hypothetical protein gene 1038 was associated with colistin resistance in Aeromonas hydrophila by reducing antibiotic function in the inner membrane, providing novel knowledge on the generation of colistin resistance.
Wendy Ankrom, Deanne Jackson Rudd, Andrea Schaeffer, Deborah Panebianco, Evan J. Friedman, Charles Tomek, S. Aubrey Stoch, Marian Iwamoto
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.00935-21

Abstract:
MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor in clinical development with potential for once-weekly oral administration for the treatment of HIV-1 infection. Two randomized, double-blind, placebo-controlled phase 1 studies in adults without HIV-1 evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of MK-8507; drug interaction with midazolam (a cytochrome P450 3A4 substrate) and food effect were also assessed. In Study 1, 16 participants received oral ascending single doses of MK-8507 (2–400 mg) or placebo in an alternating fashion. In Study 2, 24 participants received ascending single doses of MK-8507 (400–1200 mg) or placebo and multiple doses (once weekly for 3 weeks) of MK-8507 (100–400 mg) or placebo. MK-8507 pharmacokinetics were approximately dose proportional at 2–1200 mg. MK-8507 had a time to maximum concentration of 2–7 hours and a mean terminal half-life of ∼58–84 hours. MK-8507 doses ≥100 mg achieved a plasma concentration at 168 hours post-dose (7 days) associated with antiviral efficacy. A high-fat meal had no clinically meaningful effect on MK-8507 pharmacokinetics, and MK-8507 400 mg once weekly had no clinically meaningful effect on midazolam pharmacokinetics. Single and multiple doses of MK-8507 were generally well tolerated. No trends with dose and no clinically meaningful changes were observed in vital signs, electrocardiograms, and laboratory safety tests. The pharmacokinetics and safety data are supportive of once-weekly oral administration and support further clinical investigation of MK-8507 for the treatment of HIV-1 infection. Over the last 3 decades, substantial improvements have been made in oral HIV antiretroviral therapies (ART), which now offer people living with HIV (PLWH) the potential for a near-normal life expectancy (1, 2). To achieve this, individuals must maintain life-long viral suppression, which requires daily administration of efficacious medication (3). Issues surrounding tolerability, complicated regimens, and treatment fatigue from daily dosing can lead to poor adherence and suboptimal viral suppression (3–6). Regimens can become complex when there is the need to take multiple pills, requirement to take a medication fasted or with food, or the potential for interactions with other medications, including those required to treat HIV-related comorbidities (3, 78). New treatment options that are not only highly effective but also offer excellent tolerability, a high barrier to resistance, favorable drug interaction profiles, and the potential for less frequent dosing remain the focus of much clinical research (7, 9). While 1 pill once a day meets the needs of many PLWH, for others daily administration poses challenges, including treatment fatigue and daily reminders and/or stigma associated with ART (10, 11). While treatment regimens that can be taken less often than daily are attractive to many PLWH, the long-acting injectable combination of cabotegravir/rilpivirine is currently the only treatment option available without daily dosing; however, administration requires injection by a health care professional (12), potentially posing other challenges.
Arturo Luna-Tapia, Josie E. Parker, Steven L. Kelly,
Antimicrobial Agents and Chemotherapy; https://doi.org/10.1128/aac.01044-21

Abstract:
The azole antifungals inhibit sterol 14α-demethylase (S14DM), leading to depletion of cellular ergosterol and the synthesis of an aberrant sterol-diol that disrupts membrane function. In Candida albicans , sterol diol production is catalyzed by the C-5 sterol desaturase enzyme encoded by ERG3 . Accordingly, mutations that inactivate ERG3 enable the fungus to grow in the presence of the azoles. The purpose of this study was to compare the propensity of C-5 sterol desaturases from different fungal pathogens to produce the toxic diol upon S14DM inhibition and thus contribute to antifungal efficacy. The coding sequences of ERG3 homologs from C. albicans ( CaERG3 ), Candida glabrata ( CgERG3 ), Candida auris ( CaurERG3 ), Cryptococcus neoformans ( CnERG3 ), Aspergillus fumigatus ( AfERG3A-C ) and Rhizopus delemar ( RdERG3A/B ) were expressed in a C. albicans erg3Δ/Δ mutant to facilitate comparative analysis. All but one of the Erg3p-like proteins (AfErg3C) at least partially restored sterol C-5 desaturase activity, and to corresponding degrees rescued the stress and hyphal growth defects of the C. albicans erg3Δ/Δ mutant - confirming functional equivalence. Each C-5 desaturase enzyme conferred markedly different responses to fluconazole exposure in terms of the minimal inhibitory concentration (MIC) and residual growth observed at supra-MIC concentrations. Upon fluconazole-mediated inhibition of S14DM, the strains expressing each homolog also produced varying levels of 14α-methylergosta-8,24(28)-dien-3β,6α-diol. The RdErg3A and AfErg3A proteins are notable for low levels of sterol diol production and failing to confer appreciable azole sensitivity upon the C. albicans erg3Δ/Δ mutant. These findings suggest that species-specific properties of C5-sterol desaturase may be an important determinant of intrinsic azole sensitivity.
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.
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.
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.
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.
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.
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.
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.
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