Journal Article

A deletion in the RD105 region confers resistance to multiple drugs in Mycobacterium tuberculosis

Lu, Junmei, Feng, Yonghong, Liu, Zhonghua, Yang, Hua, Zheng, Ruijuan, Qin, Lianhua, Huang, Xiaochen, Hu, Zhongyi, Ge, Baoxue, Wang, Jie

2019

Overview

Background The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), especially those that are multidrug resistant poses a serious threat to global tuberculosis control. However, the mechanism underlying the occurrence of drug resistance against more than one drug is poorly understood. Given that the Beijing/W strains are associated with outbreaks and multidrug resistance, they may harbor a genetic advantage and provide useful insight into the disease. One marker found in all Beijing/W Mtb strains is a deletion of RD105 region that results in a gene fusion, Rv0071/74, with a variable number (3–9 m) of VDP (V: Val, D: Asp; P: Pro) repeats (coded by gtggacccg repeat sequences) at the N-terminal. Here, we report that this variable number of VDP repeats in Rv0071/74 regulates the development of multidrug resistance. Results We collected and analyzed 1255 Beijing/W clinical strains. The results showed that the number of VDP repeats in Rv0071/74 was related to the development of multidrug resistance, and the deletion of Rv0071/74-9 m from Beijing/W clinical strain restored drug susceptibility. Rv0071/74-9 m also increased resistance to multiple drugs when transferred to different mycobacterial strains. Cell-free assays indicate that the domain carrying 4–9 VDP repeats (4–9 m) showed a variable binding affinity with peptidoglycan and Rv0071/74 cleaves peptidoglycan. Furthermore, Rv0071/74-9 m increased cell wall thickness and reduced the intracellular concentration of antibiotics. Conclusions These findings not only identify Rv0071/74 with VDP repeats as a newly identified multidrug resistance gene but also provide a new model for the development of multiple drug resistance.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Antibiotics / Antitubercular agents / Biomedical and Life Sciences / Cell division / Cell walls / Clonal deletion / Drug resistance / Drug Resistance, Multiple, Bacterial - genetics / Drugs / Gene deletion / Gene fusion / Genes / Genetic aspects / Genotype / Life Sciences / Microbial drug resistance / Multidrug resistance / Multiple-drug resistance / Mutation / Mycobacterium tuberculosis / Mycobacterium tuberculosis - drug effects / Mycobacterium tuberculosis - genetics / Outbreaks / Peptidoglycans / Physiological aspects / RD105 region / Research Article / Rv0071/74-9 m fusion gene / Sequence Deletion / Sequences / Staphylococcus infections / Tuberculosis / Wall thickness