Missense Mutations in the CrrB Protein Mediate Odilorhabdin Derivative Resistance in Klebsiella pneumoniae
| Autor: | Lilia Boucinha, Emilie Lessoud, Lucile Pantel, Maxime Gualtieri, Anne Lanois, Emilie Racine, Alain Givaudan, Paulo Juarez, Marine Serri |
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| Přispěvatelé: | Nosopharm, Smaltis SAS - R&D Department, MaaT Pharma [Lyon], Evotec ID [Lyon], Diversité, Génomes & Interactions Microorganismes - Insectes [Montpellier] (DGIMI), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
0303 health sciences biology 030306 microbiology Chemistry Klebsiella pneumoniae Mutant ATP-binding cassette transporter biology.organism_classification Molecular biology Enterobacteriaceae [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology 3. Good health 03 medical and health sciences Response regulator Infectious Diseases Plasmid [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Pharmacology (medical) Bacterial outer membrane Gene 030304 developmental biology |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2021, 65 (5), ⟨10.1128/AAC.00139-21⟩ |
| ISSN: | 0066-4804 1098-6596 |
| Popis: | International audience; NOSO-502 is a preclinical antibiotic candidate of the odilorhabdin class. This compound exhibits activity against Enterobacteriaceae pathogens, including carbapenemase-producing bacteria and most of the colistin (CST)-resistant strains. Among a collection of CST-resistant Klebsiella pneumoniae strains harboring mutations in the genes pmrAB , mgrB , phoPQ , and crrB , only those bearing mutations in the gene crrB were found to be resistant to NOSO-502. CrrB is a histidine kinase which acts with the response regulator CrrA to modulate the PmrAB system, which induces the restructuring of lipopolysaccharide on the outer membrane and thus leads to CST resistance. Moreover, crrB mutations also enhance the transcription of neighboring genes, such as H239_3063 , encoding an ABC transporter transmembrane region, H239_3064 , encoding a putative efflux pump also known as KexD, and H239_3065 , encoding an N -acetyltransferase. To elucidate the mechanism of resistance to NOSO-502 induced by CrrB missense mutations in K. pneumoniae , mutants of NCTC 13442 and ATCC BAA-2146 strains resistant to NOSO-502 and CST with single amino acid substitutions in CrrB (S8N, F33Y, Y34N, W140R, N141I, P151A, P151L, P151S, P151T, or F303Y) were selected. Full susceptibility to NOSO-502 was restored in crrA - or crrB -deleted K. pneumoniae NCTC 13442 CrrB (P151L) mutants, confirming the role of CrrAB in controlling this resistance pathway. Deletion of kexD (but not other neighboring genes) in the same mutant also restored NOSO-502-susceptibility. Upregulation of the kexD gene expression was observed for all CrrB mutants. Finally, plasmid expression of kexD in a K. pneumoniae strain missing the locus crrABC and kexD significantly increased resistance to NOSO-502. |
| Databáze: | OpenAIRE |
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