Sakatos, AlexandraBabunovic, GregoryChase, MichaelDills, AlexanderLeszyk, JohnRosebrock, TracyBryson, BryanFortune, Sarah2018-06-272018Sakatos, Alexandra, Gregory H. Babunovic, Michael R. Chase, Alexander Dills, John Leszyk, Tracy Rosebrock, Bryan Bryson, and Sarah M. Fortune. 2018. “Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria.” Science Advances 4 (5): eaao1478. doi:10.1126/sciadv.aao1478. http://dx.doi.org/10.1126/sciadv.aao1478.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160376There is increasing evidence that phenotypically drug-resistant bacteria may be important determinants of antibiotic treatment failure. Using high-throughput imaging, we defined distinct subpopulations of mycobacterial cells that exhibit heritable but semi-stable drug resistance. These subpopulations have distinct transcriptional signatures and growth characteristics at both bulk and single-cell levels, which are also heritable and semi-stable. We find that the mycobacterial histone-like protein HupB is required for the formation of these subpopulations. Using proteomic approaches, we further demonstrate that HupB is posttranslationally modified by lysine acetylation and lysine methylation. Mutation of a single posttranslational modification site specifically abolishes the formation of one of the drug-resistant subpopulations of cells, providing the first evidence in prokaryotes that posttranslational modification of a bacterial nucleoid-associated protein may epigenetically regulate cell state.en-USSciAdv r-articlesMicrobiologyJournal Article2018-06-2710.1126/sciadv.aao1478