Ilin Aleksandr I, Kulmanov Murat E, Korotetskiy Ilya S, Islamov Rinat A, Akhmetova Gulshara K, Lankina Marina V, Reva Oleg N
Scientific Center for Anti-Infectious DrugsAlmaty, Kazakhstan.
Department of Biochemistry, Centre for Bioinformatics and Computational Biology, University of PretoriaPretoria, South Africa.
Front Cell Infect Microbiol. 2017 May 8;7:151. doi: 10.3389/fcimb.2017.00151. eCollection 2017.
Drug induced reversion of antibiotic resistance is a promising way to combat multidrug resistant infections. However, lacking knowledge of mechanisms of drug resistance reversion impedes employing this approach in medicinal therapies. Induction of antibiotic resistance reversion by a new anti-tuberculosis drug FS-1 has been reported. FS-1 was used in this work in combination with standard anti-tuberculosis antibiotics in an experiment on laboratory guinea pigs infected with an extensively drug resistant (XDR) strain SCAID 187.0. During the experimental trial, genetic changes in the population were analyzed by sequencing of isolates followed by variant calling. In total 11 isolates obtained from different groups of infected animals at different stages of disease development and treatment were sequenced. It was found that despite the selective pressure of antibiotics, FS-1 caused a counter-selection of drug resistant variants that speeded up the recovery of the infected animals from XDR tuberculosis. Drug resistance mutations reported in the genome of the initial strain remained intact in more sensitive isolates obtained in this experiment. Variant calling in the sequenced genomes revealed that the drug resistance reversion could be associated with a general increase in genetic heterogeneity of the population of . Accumulation of mutations in PpsA and PpsE subunits of phenolpthiocerol polyketide synthase was observed in the isolates treated with FS-1 that may indicate an increase of persisting variants in the population. It was hypothesized that FS-1 caused an active counter-selection of drug resistant variants from the population by aggravating the cumulated fitness cost of the drug resistance mutations. Action of FS-1 on drug resistant bacteria exemplified the theoretically predicted induced synergy mechanism of drug resistance reversion. An experimental model to study the drug resistance reversion phenomenon is hereby introduced.
药物诱导的抗生素耐药性逆转是对抗多重耐药感染的一种有前景的方法。然而，由于缺乏对耐药性逆转机制的了解，阻碍了这种方法在药物治疗中的应用。已有报道称一种新型抗结核药物FS-1可诱导抗生素耐药性逆转。在这项研究中，FS-1与标准抗结核抗生素联合用于感染广泛耐药（XDR）菌株SCAID 187.0的实验豚鼠。在实验过程中，通过对分离株进行测序并随后进行变异检测来分析群体中的基因变化。总共对从疾病发展和治疗不同阶段的不同感染动物组中获得的11个分离株进行了测序。结果发现，尽管存在抗生素的选择压力，但FS-1导致耐药变体的反向选择，加速了感染动物从XDR结核病中恢复。在该实验中获得的更敏感的分离株中，初始菌株基因组中报道的耐药性突变保持不变。对测序基因组进行变异检测发现，耐药性逆转可能与群体遗传异质性的普遍增加有关。在用FS-1处理的分离株中观察到酚硫酯醇聚酮合酶的PpsA和PpsE亚基中的突变积累，这可能表明群体中持续存在的变体增加。据推测，FS-1通过加重耐药性突变累积的适应性成本，导致从群体中对耐药变体进行积极的反向选择。FS-1对耐药细菌的作用例证了理论上预测的耐药性逆转诱导协同机制。特此引入一个研究耐药性逆转现象的实验模型。
