Roson-Calero Natalia, Lucas Jimmy, Gomis-Font María A, de Pedro-Jové Roger, Oliver Antonio, Ballesté-Delpierre Clara, Vila Jordi
Barcelona Institute for Global Health (ISGlobal), 08036 Barcelona, Spain.
Department of Basic Clinical Practice, School of Medicine, University of Barcelona, 08036 Barcelona, Spain.
Antibiotics (Basel). 2024 Dec 1;13(12):1147. doi: 10.3390/antibiotics13121147.
: is a globally emerging pathogen with widespread antimicrobial resistance driven by multiple mechanisms, such as altered expression of efflux pumps like AdeABC, placing it as a priority for research. Driven by the lack of new treatments, alternative approaches are being explored to combat its infections, among which efficacy-enhancing adjuvants can be found. This study presents and characterizes MV6, a synthetic cyclic peptide that boosts aminoglycoside efficacy. : MV6's activity was assessed through antimicrobial susceptibility testing in combination with different antibiotic classes against strains characterized by PCR and RT-qPCR. PAβN served as a reference efflux pump inhibitor. Synergy was evaluated using checkerboard assays, and spontaneous mutants were generated with netilmicin with/without MV6 (100 mg/L). Whole-genome sequencing and variant calling analysis were then performed. : MV6 presented low antimicrobial activity in with MICs higher than 2048 mg/L. MV6 showed a better boosting effect for aminoglycosides, especially netilmicin, exceeding that of PAβN. Checkerboard assays confirmed a strong synergy between netilmicin and MV6, and a significant correlation was found between netilmicin MIC and overexpression, which was mitigated by the presence of MV6. MV6 reduced, by 16-fold, the mutant prevention concentration of netilmicin. Mutations in a TetR-family regulator and ABC-binding proteins were found in both groups, suggesting a direct or indirect implication of these proteins in the resistance acquisition process. : MV6 lacks intrinsic antimicrobial activity, minimizing selective pressure, yet enhances netilmicin's effectiveness except for strain 210, which lacks the AdeABC efflux pump. Resistant mutants indicate specific aminoglycoside resistance mechanisms involving efflux pump mutations, suggesting synergistic interactions. Further research, including transcriptomic analysis, is essential to elucidate MV6's role in enhancing netilmicin efficacy and its resistance mechanisms.
是一种全球范围内新兴的病原体，具有多种机制驱动的广泛抗菌耐药性，例如外排泵（如AdeABC）表达改变，这使其成为研究重点。由于缺乏新的治疗方法，人们正在探索替代方法来对抗其感染，其中可以找到增强疗效的佐剂。本研究介绍并表征了MV6，一种增强氨基糖苷类药物疗效的合成环肽。MV6的活性通过抗菌药敏试验进行评估，该试验将不同抗生素类别与通过PCR和RT-qPCR表征的菌株相结合。PAβN用作参考外排泵抑制剂。使用棋盘法评估协同作用，并使用奈替米星（有/无MV6，100mg/L）产生自发突变体。然后进行全基因组测序和变异调用分析。MV6在中表现出低抗菌活性，MIC高于2048mg/L。MV6对氨基糖苷类药物，尤其是奈替米星，表现出更好的增强作用，超过了PAβN。棋盘法证实奈替米星与MV6之间有很强的协同作用，并且发现奈替米星MIC与过表达之间存在显著相关性，而MV6的存在减轻了这种相关性。MV6将奈替米星的突变预防浓度降低了16倍。在两组中均发现了TetR家族调节因子和ABC结合蛋白的突变，表明这些蛋白在耐药性获得过程中存在直接或间接影响。MV6缺乏内在抗菌活性，使选择性压力最小化，但除了缺乏AdeABC外排泵的210菌株外，可增强奈替米星的有效性。耐药突变体表明涉及外排泵突变的特定氨基糖苷类耐药机制，提示存在协同相互作用。进一步的研究，包括转录组分析，对于阐明MV6在增强奈替米星疗效及其耐药机制中的作用至关重要。
