Pantel Lucile, Juarez Paulo, Serri Marine, Boucinha Lilia, Lessoud Emilie, Lanois Anne, Givaudan Alain, Racine Emilie, Gualtieri Maxime
Nosopharm, 110 allée Charles Babbage, Espace Innovation 2, Nîmes, France.
Research and Development Department, Smaltis SAS, Besançon, France.
Antimicrob Agents Chemother. 2023 May 1;65(5). doi: 10.1128/AAC.00139-21. Epub 2021 Mar 8.
NOSO-502 is a preclinical antibiotic candidate of the Odilorhabdin class. This compound exhibits activity against pathogens, including carbapenemase-producing bacteria and most of the Colistin (CST)-resistant strains. Among a collection of CST-resistant strains harboring mutations on genes , , , and , only those bearing mutations in gene 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 finally induces the restructuring of the lipopolysaccharide present on the outer membrane and thus leading to CST resistance. Moreover, mutations also enhance the transcription of neighboring genes such as H239_3063, an ABC transporter transmembrane region; H239_3064, a putative efflux pump also known as KexD; and H239_3065, a -acetyltransferase.To elucidate the mechanism of resistance to NOSO-502 induced by CrrB missense mutations in , 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, F303Y) were selected. Full susceptibility to NOSO-502 was restored in or deleted NCTC 13442 CrrB(P151L) mutants, confirming the role of CrrAB in controlling this resistance pathway. Deletion of (but no other neighboring genes) in the same mutant also restored NOSO-502-susceptibility. Upregulation of the gene expression was observed for all CrrB mutants. Finally, plasmid expression of in a strain missing the locus and significantly increased resistance to NOSO-502.
NOSO-502是一种临床前的奥德菌素类抗生素候选药物。该化合物对包括产碳青霉烯酶细菌和大多数耐黏菌素（CST）菌株在内的病原体具有活性。在一组在基因、、、和上发生突变的耐CST菌株中，仅发现那些在基因上发生突变的菌株对NOSO-502耐药。CrrB是一种组氨酸激酶，它与应答调节因子CrrA共同作用来调节PmrAB系统，最终诱导外膜上脂多糖的重构，从而导致对CST的耐药性。此外，突变还增强了邻近基因的转录，如ABC转运体跨膜区域的H239_3063；一种也被称为KexD的推定外排泵H239_3064；以及一种乙酰转移酶H239_3065。为了阐明由CrrB错义突变在中诱导的对NOSO-502的耐药机制，选择了对NOSO-502和CST耐药且CrrB中具有单氨基酸取代（S8N、F33Y、Y34N、W140R、N141I、P151A、P151L、P151S、P151T、F303Y）的NCTC 13442和ATCC BAA-2146菌株的突变体。在缺失CrrB（P151L）的NCTC 13442突变体中，对NOSO-502的完全敏感性得以恢复，证实了CrrAB在控制这一耐药途径中的作用。在同一突变体中缺失（但不包括其他邻近基因）也恢复了对NOSO-502的敏感性。在所有CrrB突变体中均观察到基因表达上调。最后，在缺失基因座和的菌株中通过质粒表达显著增加了对NOSO-502的耐药性。
