Five New or Repurposed Drugs (NRDs) were approved in the last decade for treatment of multi-drug resistant tuberculosis: bedaquiline, clofazimine, linezolid, delamanid, and pretomanid. Unfortunately, resistance to these drugs emerged faster than anticipated, potentially due to preexisting resistance in naïve strains. Previous investigations into the rapid emergence have mostly included short variants. For the first time, we utilize de novo-assembled genomes, and systematically include Structural Variations (SV) and heterogeneity to comprehensively study this rapid emergence. We show high prevalence of preexisting resistance, identify novel markers of resistance, and lay the foundation for preventing preexisting resistance in future drug development.

中文翻译：

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广泛的功能丧失突变，表明先前存在对新的或重新调整用途的抗结核药物的耐药性


在过去十年中，五种新药或再利用药物 （NRD） 被批准用于治疗耐多药结核病：贝达喹啉、氯法齐明、利奈唑胺、德拉马尼和普雷托马尼。不幸的是，对这些药物的耐药性出现得比预期的要快，这可能是由于幼稚菌株中先前存在的耐药性。以前对快速出现的研究大多包括短变体。我们首次利用从头组装的基因组，并系统地包括结构变异 （SV） 和异质性来全面研究这种快速出现。我们显示了预先存在的耐药性的高患病率，确定了新的耐药性标志物，并为在未来的药物开发中预防预先存在的耐药性奠定了基础。