Peptidoglycan synthesis inMycobacterium tuberculosisis organized into networks with varying drug susceptibility

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 42; pp. 13087 - 13092
• Main Authors: Kieser, Karen J., Baranowski, Catherine, Chao, Michael C., Long, Jarukit E., Sassetti, Christopher M., Waldor, Matthew K., Sacchettini, James C., Ioerger, Thomas R., Rubin, Eric J.
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 20.10.2015
• ISSN: 0027-8424; 1091-6490

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 pathogenMycobacterium tuberculosis(Mtb). The principle PG synthetic enzymes have similar and, at times, overlapping functions. To determine how these are functionally organized,we carried outwhole-genome transposon mutagenesis screens inMtbstrains deleted forponA1, ponA2,andldtB, 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 inMtb. Either PonA1 or PonA2 is required for growth ofMtb, 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,Mtbuses alternative pathways to produce PG, each with its own biochemical characteristics and vulnerabilities.