title: Lipopolysaccharide loss produces partial colistin dependence and collateral sensitivity to azithromycin, rifampicin and vancomycin in Acinetobacter baumannii.
abstract: Treatment options for multidrug-resistant (MDR) strains of Acinetobacter baumannii that acquire resistance to colistin are limited. Acinetobacter baumannii can become highly resistant to colistin through complete loss of lipopolysaccharide (LPS) owing to mutations in the genes encoding the first three enzymes involved in lipid A biosynthesis (lpxA, lpxC and lpxD). The objective of this study was to characterise the susceptibility to 15 clinically relevant antibiotics and 6 antimicrobial peptides (AMPs) of MDR A. baumannii clinical isolates that acquired colistin resistance due to mutations in lpxA, lpxC and lpxD as well as their colistin-susceptible counterparts. A dramatic increase in antibiotic susceptibility (≥16-fold increase) was observed upon LPS loss for azithromycin, rifampicin and vancomycin, whereas a moderate increase in susceptibility was seen for amikacin, ceftazidime, imipenem, cefepime and meropenem. Importantly, concentrations ranging from 8 mg/L to 32 mg/L of the six AMPs were able to reduce bacterial viability by ≥3 log10 in growth curve assays. We also demonstrate that colistin resistance results in partial colistin dependence for growth in LPS-deficient strains containing mutations in lpxA, lpxC and lpxD, but not when colistin resistance occurs via LPS modification due to mutations in the PmrA/B two-component system. The results of this study indicate that loss of LPS expression results in collateral sensitivity to azithromycin, rifampicin and vancomycin, and that the six AMPs tested retain activity against LPS-deficient strains, indicating that these antibiotics may be viable treatment options for infections caused by these strains.
authors.affiliation: Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: García-Quintanilla
authors.affiliation: Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Carretero-Ledesma
authors.affiliation: Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Moreno-Martínez
authors.affiliation: Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: Reyes
authors.initials: R
authors.lastname: Martín-Peña
authors.affiliation: Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Pachón
authors.affiliation: Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain. Electronic address: mcconnell.mike75@gmail.com.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McConnell
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D003091:Colistin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D006801:Humans; D008050:Lipid A / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology*; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; D014640:Vancomycin; D017963:Azithromycin; D012293:Rifampin; D003091:Colistin
keywords: Acinetobacter baumannii; Antibiotics; Antimicrobial peptides; Colistin resistance; Collateral sensitivity