Eoh Hyungjin, Lee Jae Jin, Swanson Daniel, Lee Sun-Kyung, Dihardjo Stephanie, Lee Gi Yong, Sree Gelle, Maskill Emily, Taylor Zachary, Van Nieuwenhze Michael, Singh Abhyudai, Lee Jong-Seok, Eum Seok-Yong, Cho Sang-Nae, Swarts Benjamin
University of Southern California.
Central Michigan University.
Res Sq. 2024 Sep 13:rs.3.rs-4999164. doi: 10.21203/rs.3.rs-4999164/v1.
Drug-resistance (DR) in many bacterial pathogens often arises from the repetitive formation of drug-tolerant bacilli, known as persisters. However, it is unclear whether (Mtb), the bacterium that causes tuberculosis (TB), undergoes a similar phenotypic transition. Recent metabolomics studies have identified that a change in trehalose metabolism is necessary for Mtb to develop persisters and plays a crucial role in metabolic networks of DR-TB strains. The present study used Mtb mutants lacking the trehalose catalytic shift and showed that the mutants exhibited a significantly lower frequency of the emergence of DR mutants compared to wildtype, due to reduced persister formation. The trehalose catalytic shift enables Mtb persisters to survive under bactericidal antibiotics by increasing metabolic heterogeneity and drug tolerance, ultimately leading to development of DR. Intriguingly, rifampicin (RIF)-resistant bacilli exhibit cross-resistance to a second antibiotic, due to a high trehalose catalytic shift activity. This phenomenon explains how the development of multidrug resistance (MDR) is facilitated by the acquisition of RIF resistance. In this context, the heightened risk of MDR-TB in the lineage 4 HN878 W-Beijing strain can be attributed to its greater trehalose catalytic shift. Genetic and pharmacological inactivation of the trehalose catalytic shift significantly reduced persister formation, subsequently decreasing the incidence of MDR-TB in HN878 W-Beijing strain. Collectively, the trehalose catalytic shift serves as an intrinsic factor of Mtb responsible for persister formation, cross-resistance to multiple antibiotics, and the emergence of MDR-TB. This study aids in the discovery of new TB therapeutics by targeting the trehalose catalytic shift of Mtb.
许多细菌病原体中的耐药性（DR）通常源于耐药性杆菌（即持留菌）的反复形成。然而，尚不清楚导致结核病（TB）的结核分枝杆菌（Mtb）是否经历类似的表型转变。最近的代谢组学研究已确定，海藻糖代谢的变化是Mtb形成持留菌所必需的，并且在耐多药结核菌株的代谢网络中起关键作用。本研究使用缺乏海藻糖催化转变的Mtb突变体，结果表明，与野生型相比，这些突变体中耐药突变体出现的频率显著降低，这是由于持留菌形成减少所致。海藻糖催化转变通过增加代谢异质性和耐药性，使Mtb持留菌能够在杀菌抗生素作用下存活，最终导致耐药性的产生。有趣的是，耐利福平（RIF）的杆菌由于具有高海藻糖催化转变活性，对第二种抗生素表现出交叉耐药性。这一现象解释了获得RIF耐药性如何促进多药耐药性（MDR）的发展。在这种情况下，4型HN878 W-北京菌株中MDR-TB风险增加可归因于其更大的海藻糖催化转变。海藻糖催化转变的基因和药理学失活显著减少了持留菌的形成，随后降低了HN878 W-北京菌株中MDR-TB的发生率。总的来说，海藻糖催化转变是Mtb形成持留菌、对多种抗生素产生交叉耐药性以及MDR-TB出现的内在因素。这项研究有助于通过靶向Mtb的海藻糖催化转变来发现新的结核病治疗方法。
