Antagonistic Interactions of Pseudomonas aeruginosa Antibiotic Resistance Mechanisms in Planktonic but Not Biofilm Growth
- 1 October 2011
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 55 (10), 4560-4568
- https://doi.org/10.1128/aac.00519-11
Abstract
Pseudomonas aeruginosa has an extraordinary capacity to evade the activity of antibiotics through a complex interplay of intrinsic and mutation-driven resistance pathways, which are, unfortunately, often additive or synergistic, leading to multidrug (or even pandrug) resistance. However, we show that one of these mechanisms, overexpression of the MexCD-OprJ efflux pump (driven by inactivation of its negative regulator NfxB), causes major changes in the cell envelope physiology, impairing the backbone of P. aeruginosa intrinsic resistance, including the major constitutive (MexAB-OprM) and inducible (MexXY-OprM) efflux pumps and the inducible AmpC β-lactamase. Moreover, it also impaired the most relevant mutation-driven β-lactam resistance mechanism (constitutive AmpC overexpression), through a dramatic decrease in periplasmic β-lactamase activity, apparently produced by an abnormal permeation of AmpC out of the cell. While these results could delineate future strategies for combating antibiotic resistance in cases of acute nosocomial infections, a major drawback for the potential exploitation of the described antagonistic interaction between resistance mechanisms came from the differential bacterial physiology characteristics of biofilm growth, a hallmark of chronic infections. Although the failure to concentrate AmpC activity in the periplasm dramatically limits the protection of the targets (penicillin-binding proteins [PBPs]) of β-lactams at the individual cell level, the expected outcome for cells growing as biofilm communities, which are surrounded by a thick extracellular matrix, was less obvious. Indeed, our results showed that AmpC produced by nfxB mutants is protective in biofilm growth, suggesting that the permeation of AmpC into the matrix protects biofilm communities against β-lactams.Keywords
This publication has 36 references indexed in Scilit:
- Activity of a New Cephalosporin, CXA-101 (FR264205), against β-Lactam-Resistant Pseudomonas aeruginosa Mutants Selected In Vitro and after Antipseudomonal Treatment of Intensive Care Unit PatientsAntimicrobial Agents and Chemotherapy, 2010
- Molecular basis of pyoverdine siderophore recycling in Pseudomonas aeruginosaProceedings of the National Academy of Sciences of the United States of America, 2009
- Antibacterial-ResistantPseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance MechanismsClinical Microbiology Reviews, 2009
- Azithromycin in Pseudomonas aeruginosa Biofilms: Bactericidal Activity and Selection of nfxB MutantsAntimicrobial Agents and Chemotherapy, 2009
- β-Lactam Resistance Response Triggered by Inactivation of a Nonessential Penicillin-Binding ProteinPLoS Pathogens, 2009
- MexCD-OprJ Multidrug Efflux System of Pseudomonas aeruginosa : Involvement in Chlorhexidine Resistance and Induction by Membrane-Damaging Agents Dependent upon the AlgU Stress Response Sigma FactorAntimicrobial Agents and Chemotherapy, 2008
- Benefit of Having MultipleampDGenes for Acquiring β-Lactam Resistance without Losing Fitness and Virulence inPseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2008
- Resistance and Virulence of Pseudomonas aeruginosa Clinical Strains Overproducing the MexCD-OprJ Efflux PumpAntimicrobial Agents and Chemotherapy, 2008
- The Neglected Intrinsic Resistome of Bacterial PathogensPLOS ONE, 2008
- Stepwise Upregulation of thePseudomonas aeruginosaChromosomal Cephalosporinase Conferring High-Level β-Lactam Resistance Involves Three AmpD HomologuesAntimicrobial Agents and Chemotherapy, 2006