Mokrousov Igor, Angelova Violina T, Slavchev Ivaylo, Bezruchko Mikhail V, Dimitrov Simeon, Polev Dmitrii E, Dobrikov Georgi M, Valcheva Violeta
St. Petersburg Pasteur Institute, 197101 St. Petersburg, Russia.
Faculty of Pharmacy, Medical University, 1000 Sofia, Bulgaria.
Antibiotics (Basel). 2025 Feb 22;14(3):225. doi: 10.3390/antibiotics14030225.
New anti-tuberculosis compounds are needed to treat patients infected with multi- or extensively drug-resistant strains. Studies based on spontaneous in vitro mutagenesis can provide insights into the possible modes of action and resistance mechanisms of such new compounds. We evaluated the primary response of in vitro to the action of new aroylhydrazones and nitrofuroylamides. : The reference strain H37Rv was cultured on solid media with compounds at increased concentrations relative to MIC. Resistant clones were investigated using whole-genome sequencing and bioinformatics tools to assess the role and potential impact of identified mutations. : Some of the mutations are significant (based on in silico analysis), located in essential genes, and therefore of particular interest. Frameshift mutations were observed in (i) , which is associated with starvation-induced drug tolerance and persistence in mice, and (ii) , which has been described as a switch on/off mutation associated with drug tolerance. Nonsynonymous substitutions were found in , which belongs to the Mmp protein family involved in transport and drug efflux, and in , encoding the translation initiation factor IF-2. : The primary adaptation of to the selective pressure of the tested compounds is complex and multifaceted. It involves multiple unrelated genes and pathways linked to non-specific drug tolerance, efflux systems, or mechanisms counteracting oxidative stress.
需要新型抗结核化合物来治疗多重耐药或广泛耐药菌株感染的患者。基于自发体外诱变的研究可以为这类新化合物的可能作用方式和耐药机制提供见解。我们评估了体外对新型芳酰腙和硝呋罗酰胺作用的初始反应。：将参考菌株H37Rv在固体培养基上培养，培养基中化合物浓度相对于最低抑菌浓度（MIC）升高。使用全基因组测序和生物信息学工具研究耐药克隆，以评估已鉴定突变的作用和潜在影响。：一些突变很显著（基于计算机分析），位于必需基因中，因此特别令人关注。在（i） 中观察到移码突变，该基因与饥饿诱导的药物耐受性和小鼠体内的持续存在有关，以及（ii） 中，该基因被描述为与药物耐受性相关的开关突变。在属于参与转运和药物外排的Mmp蛋白家族的 中以及在编码翻译起始因子IF-2的 中发现了非同义替换。：H37Rv对受试化合物选择压力的初始适应性是复杂且多方面的。它涉及多个与非特异性药物耐受性、外排系统或对抗氧化应激机制相关的不相关基因和途径。
