文章基本信息

标题：Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility
本地全文：下载
作者：Karen J. Kieser ; Catherine Baranowski ; Michael C. Chao 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：42
页码：13087-13092
DOI：10.1073/pnas.1514135112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe rise of drug-resistant Mycobacterium tuberculosis (Mtb) underscores the critical need for a better understanding of essential physiological processes. Among these is cell-wall synthesis, the target of many antibiotics. To understand how Mtb orchestrates synthesis of its cell wall, we performed whole-genome interaction studies in cells with different peptidoglycan synthesis mutations. We found that different enzymes become required for bacterial growth in{Delta} ponA1,{Delta} ponA2, or{Delta} ldtB cells, suggesting that discrete cell envelope biogenesis networks exist in Mtb. Furthermore, we show that these networks' enzymes are differentially susceptible to cell-wall-active drugs. Our data provide insight into the essential processes of cell-wall synthesis in Mtb and highlight the role of different synthesis networks in antibiotic tolerance. Peptidoglycan (PG), a complex polymer composed of saccharide chains cross-linked by short peptides, is a critical component of the bacterial cell wall. PG synthesis has been extensively studied in model organisms but remains poorly understood in mycobacteria, a genus that includes the important human pathogen Mycobacterium tuberculosis (Mtb). The principle PG synthetic enzymes have similar and, at times, overlapping functions. To determine how these are functionally organized, we carried out whole-genome transposon mutagenesis screens in Mtb strains deleted for ponA1, ponA2, and ldtB, major PG synthetic enzymes. We identified distinct factors required to sustain bacterial growth in the absence of each of these enzymes. We find that even the homologs PonA1 and PonA2 have unique sets of genetic interactions, suggesting there are distinct PG synthesis pathways in Mtb. Either PonA1 or PonA2 is required for growth of Mtb, but both genetically interact with LdtB, which has its own distinct genetic network. We further provide evidence that each interaction network is differentially susceptible to antibiotics. Thus, Mtb uses alternative pathways to produce PG, each with its own biochemical characteristics and vulnerabilities.
关键词：Mycobacterium tuberculosis ; transposon sequencing ; genetic interaction ; peptidoglycan ; cell wall