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Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity

The mycobacterial protein LamA functions as an inhibitor of cell wall synthesis at the nascent cell pole, contributing to asymmetry in polar growth, and could represent a much-needed target for the development of anti-tuberculosis therapies. Role for LamA in antibiotic tolerance Here the authors rep...

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Bibliographic Details
Published in:Nature (London) 2017-06, Vol.546 (7656), p.153-157
Main Authors: Rego, E. Hesper, Audette, Rebecca E., Rubin, Eric J.
Format: Article
Language:English
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Summary:The mycobacterial protein LamA functions as an inhibitor of cell wall synthesis at the nascent cell pole, contributing to asymmetry in polar growth, and could represent a much-needed target for the development of anti-tuberculosis therapies. Role for LamA in antibiotic tolerance Here the authors report the discovery of a new protein (LamA) that functions as part of the 'divisome' in mycobacteria. The authors report that LamA functions as an inhibitor of cell wall synthesis at the nascent cell pole, contributing to asymmetry in polar growth. Asymmetric growth and division increases population heterogeneity, which has been linked to antibiotic tolerance and persistent infection. Here they show that removal of LamA leads to a more uniform cell population that is more effectively killed by antibiotics. Thus, LamA represents a much-needed new target for the development of anti-tuberculosis therapies. Microorganisms are often studied as populations but the behaviour of single, individual cells can have important consequences. For example, tuberculosis, caused by the bacterial pathogen Mycobacterium tuberculosis , requires months of antibiotic therapy even though the bulk of the bacterial population dies rapidly. Shorter courses lead to high rates of relapse because subpopulations of bacilli can survive despite being genetically identical to those that are easily killed 1 . In fact, mycobacteria create variability each time a cell divides, producing daughter cells with different sizes and growth rates 2 , 3 . The mechanism(s) that underlie this high-frequency variation and how variability relates to survival of the population are unknown. Here we show that mycobacteria actively create heterogeneity. Using a fluorescent reporter and a fluorescence-activated cell sorting (FACS)-based transposon screen, we find that deletion of lamA , a gene of previously unknown function, decreases heterogeneity in the population by decreasing asymmetric polar growth. LamA has no known homologues in other organisms, but is highly conserved across mycobacterial species. We find that LamA is a member of the mycobacterial division complex (the ‘divisome’). It inhibits growth at nascent new poles, creating asymmetry in polar growth. The kinetics of killing individual cells that lack lamA are more uniform and more rapid with rifampicin and drugs that target the cell wall. Our results show that mycobacteria encode a non-conserved protein that controls the pattern of cell growth, resultin
ISSN:0028-0836
1476-4687
DOI:10.1038/nature22361