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Mutations in genes lpxL1 , bamA , and pmrB impair the susceptibility of cystic fibrosis strains of Pseudomonas aeruginosa to murepavadin.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Jan 10; Vol. 68 (1), pp. e0129823. Date of Electronic Publication: 2023 Dec 11. - Publication Year :
- 2024
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Abstract
- Murepavadin is a peptidomimetic exhibiting specific inhibitory activity against Pseudomonas species. In the present study, its in vitro activity was assessed on 230 cystic fibrosis (CF) strains of Pseudomonas aeruginosa isolated from 12 French hospitals, in comparison with 12 other antipseudomonal antibiotics. Although murepavadin is still in preclinical stage of development, 9.1% ( n = 21) of strains had a minimum inhibitory concentration (MIC) >4 mg/L, a level at least 128-fold higher than the modal MIC value of the whole collection (≤0.06 mg/L). Whole-genome sequencing of these 21 strains along with more susceptible isogenic counterparts coexisting in the same patients revealed diverse mutations in genes involved in the synthesis ( lpxL1 and lpxL2 ) or transport of lipopolysaccharides ( bamA , lptD , and msbA ), or encoding histidine kinases of two-component systems ( pmrB and cbrA ). Allelic replacement experiments with wild-type reference strain PAO1 confirmed that alteration of genes lpxL1 , bamA, and/or pmrB can decrease the murepavadin susceptibility from 8- to 32-fold. Furthermore, we found that specific amino acid substitutions in histidine kinase PmrB (G188D, Q105P, and D45E) reduce the susceptibility of P. aeruginosa to murepavadin, colistin, and tobramycin, three antibiotics used or intended to be used (murepavadin) in aerosols to treat colonized CF patients. Whether colistin or tobramycin may select mutants resistant to murepavadin or the opposite needs to be addressed by clinical studies.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Humans
Colistin pharmacology
Colistin therapeutic use
Pseudomonas aeruginosa
Respiratory Aerosols and Droplets
Anti-Bacterial Agents pharmacology
Anti-Bacterial Agents therapeutic use
Tobramycin pharmacology
Mutation genetics
Microbial Sensitivity Tests
Cystic Fibrosis drug therapy
Pseudomonas Infections drug therapy
Pseudomonas Infections complications
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 68
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 38092672
- Full Text :
- https://doi.org/10.1128/aac.01298-23