Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

Article Article scientifique Article Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa eng 2020-03-24 2020-03-24 author Ben Jeddou Fatma Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland.,Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland. 871739 author Falconnet Léna Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland.,Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland. 898001 Département de médecine (DEMED) author Luscher Alexandre 0009-0002-9247-7713 Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland.,Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland. 660541 Département de médecine (DEMED) author Siriwardena Thissa Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland. author Reymond Jean-Louis Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland. 742414 author Van Delden Christian Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland.,Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland. 24088 Département de médecine (DEMED) author Kohler Thilo 0000-0003-4889-9492 Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland thilo.kohler@unige.ch.,Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland. 23327 e02040-19 10.1128/AAC.02040-19 32015046 0066-4804 PMC7179292 Colistin (polymyxin E) is a last-resort antibiotic against multidrug-resistant isolates of Pseudomonas aeruginosa However, the nephro-toxicity of colistin limits its use, spurring the interest in novel antimicrobial peptides (AMP). Here, we show that the synthetic AMP-dendrimer G3KL (MW 4,531.38 Da, 15 positive charges, MIC = 8 mg/liter) showed faster killing than polymyxin B (Pmx-B) with no detectable resistance selection in P. aeruginosa strain PA14. Spontaneous mutants selected on Pmx-B, harboring loss of function mutations in the PhoQ sensor kinase gene, showed increased Pmx-B MICs and arnB operon expression (4-amino-l-arabinose addition to lipid A), but remained susceptible to dendrimers. Two mutants carrying a missense mutation in the periplasmic loop of the PmrB sensor kinase showed increased MICs for Pmx-B (8-fold) and G3KL (4-fold) but not for the dendrimer T7 (MW 4,885.64 Da, 16 positive charges, MIC = 8 mg/liter). The pmrB mutants showed increased expression of the arnB operon as well as of the speD2-speE2 -PA4775 operon, located upstream of pmrAB , and involved in polyamine biosynthesis. Exogenous supplementation with the polyamines spermine and norspermine increased G3KL and T7 MICs in a phoQ mutant background but not in the PA14 wild type. This suggests that both addition of 4-amino-l-arabinose and secretion of polyamines are required to reduce susceptibility to dendrimers, probably neutralizing the negative charges present on the lipid A and the 2-keto-3-deoxyoctulosonic acid (KDO) sugars of the lipopolysaccharide (LPS), respectively. We further show by transcriptome analysis that the dendrimers G3KL and T7 induce adaptive responses through the CprRS two-component system in PA14. AMP-dendrimers Pseudomonas aeruginosa Antimicrobial peptides Dendrimers Two-component regulatory systems Two-component systems Anti-Bacterial Agents / pharmacology Antimicrobial Cationic Peptides / pharmacology Arabinose / pharmacology Bacterial Proteins / genetics Colistin / pharmacology Dendrimers / pharmacology Drug Resistance, Multiple, Bacterial / genetics Lipopolysaccharides / chemistry Microbial Sensitivity Tests Polymyxin B / pharmacology Pseudomonas aeruginosa / drug effects Pseudomonas aeruginosa / genetics Spermine / analogs & derivatives Spermine / pharmacology Transcription Factors / genetics Dewey 616 Swiss National Science Foundation Antimicrobial peptide dendrimers (AMPD) and bicyclic peptides (AMBP) as therapeutic agents against multidrug resistant bacteria 167048 CH 54 Département de microbiologie et médecine moléculaire 21B 56 Département de médecine 221 false 235 Perception du Quorum et gènes de virulence 301 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139257 Antimicrobial agents and chemotherapy 64 4 674b1f0d-5e80-4a04-a30a-3e0fb5094939 Article (Published version) Public ben-jeddou-et-al-2020-adaptive-and-.pdf 2558087 application/pdf CC BY-4.0 38dfad8b7a8cbfa984a9cafbb6697df1d0909d083af6fd8c8c98f1ebdb610b7a 6e250901-ab0d-407e-b908-e2ef170fdc63 Appendix Public AAC.02040-19-s0001.pdf 546700 application/pdf 626c2dbd34d38b4ae55d5a15dfa5d109da850c894a42503e5b5a3c20fec99560 openAccess Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire Faculté de médecine / Section de médecine clinique / Département de médecine

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