抗結核療法新靶標:LamA蛋白

信息來源:
http://www.natureasia.com/zh-cn/nature/highlights/86158
https://www.nature.com/nature/journal/v546/n7656/full/nature22361.html

一種新型蛋白(LamA),分枝桿菌分裂體的一部分,在新生的細胞極抑制了細胞壁合成,造成了細胞極性生長的不對稱性。不對稱生長和分裂增加了種群異質性,而這一性質此前曾被發現與抗生素耐藥性和持續性感染有關。研究發現,去除LamA能帶來更統一的細胞種群,抗生素殺死這樣的種群的效率更高。因此,LamA可能是抗結核療法新靶標。

Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity
E. Hesper Rego, Rebecca E. Audette & Eric J. Rubin

Nature 546, 153–157 (01 June 2017) doi:10.1038/nature22361

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 killed1. In fact, mycobacteria create variability each time a cell divides, producing daughter cells with different sizes and growth rates2, 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, resulting in a population that is both heterogeneous and better able to survive antibiotic pressure.

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