Boudrioua Abdelhakim, Baëtz Benjamin, Desmadril Solenn, Goulard Christophe, Groo Anne-Claire, Lombard Carine, Gueulle Sabrina, Marugan Marie, Malzert-Fréon Aurélie, Hartke Axel, Li Yanyan, Giraud Caroline
Université de Caen Normandie, CBSA UR4312, F-14000 Caen, France.
Unit Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-Muséum National d'Histoire Naturelle (MNHN), 75005 Paris, France.
iScience. 2025 Jan 30;28(3):111922. doi: 10.1016/j.isci.2025.111922. eCollection 2025 Mar 21.
Antibiotic resistance is a major threat to human health and new drugs are urgently needed. Ideally, these drugs should have several cellular targets in pathogens, decreasing the risk of resistance development. We show here that two natural ribosomally synthesized lasso peptides (LPs), sviceucin and siamycin I, (1) abolish bacterial virulence of pathogenic enterococci, (2) restore vancomycin clinical susceptibility of vancomycin-resistant (VR) enterococci and in a surrogate animal model, and (3) re-sensitize VR . Mode of action (MoA) analyses showed that they do so by inhibiting the histidine kinases (HKs) FsrC and VanS controlling these phenotypes. Strains resistant to the vancomycin/LP combination were difficult to obtain, and were still fully susceptible to the anti-virulence effect of the LPs, highlighting the advantage of multiple targets. Together with the highly sought-after MoA as HK inhibitors, such properties make these lasso peptides promising candidates for the development of next generation antibiotics.
抗生素耐药性是对人类健康的重大威胁，因此迫切需要新型药物。理想情况下，这些药物应在病原体中有多个细胞靶点，以降低耐药性产生的风险。我们在此表明，两种天然核糖体合成的套索肽（LPs），即sviceucin和西阿霉素I，（1）消除致病性肠球菌的细菌毒力，（2）在替代动物模型中恢复耐万古霉素（VR）肠球菌对万古霉素的临床敏感性，以及（3）使VR重新敏感。作用模式（MoA）分析表明，它们通过抑制控制这些表型的组氨酸激酶（HKs）FsrC和VanS来实现上述作用。难以获得对万古霉素/LP组合耐药的菌株，且这些菌株对LPs的抗毒力作用仍完全敏感，这突出了多靶点的优势。连同作为HK抑制剂这一备受追捧的作用模式，这些特性使这些套索肽成为开发下一代抗生素的有前途的候选药物。
