Diisonitrile Lipopeptides Mediate Resistance to Copper Starvation in Pathogenic Mycobacteria.
Diisonitrile Lipopeptides Mediate Resistance to Copper Starvation in Pathogenic Mycobacteria.
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作者：
细菌病原体及其宿主在感染期间对关键营养物质进行激烈竞争，包括铁，铜和锌等金属。一些金属被宿主限制，一些被宿主作为抗菌剂部署。为了对抗金属限制，病原体部署了高亲和力的金属获取系统，最好的例子是铁载体来获取铁。虽然病原体的策略，以抵御高铜的毒性作用已被阐明，铜饥饿的作用和存在的铜收购系统的特点不太好。在这项研究中，我们研究了致病性分枝杆菌的二异腈查尔基在金属获取中的作用，该查尔基是由与毒性相关的nrp基因簇编码的酶合成的。nrp基因簇表达强烈诱导饥饿或螯合铜，但不饥饿锌或过量铜。结核分枝杆菌和海洋分枝杆菌菌株缺乏nrp编码的非核糖体肽合成酶，fadD10腺苷酸形成酶，或未表征的上游基因ppe1都敏感铜，但不是锌，饥饿。这种低Cu敏感性是由遗传互补或通过提供合成的二异腈chalkophore拯救。这些数据表明，分枝杆菌中的二异腈脂肽是促进在铜限制条件下存活的白垩基，并表明铜饥饿是分枝杆菌的相关应激。宿主体内的肺结核
Bacterial pathogens and their hosts engage in intense competition for critical nutrients during infection, including metals such as iron, copper, and zinc. Some metals are limited by the host, and some are deployed by the host as antimicrobials. To counter metal limitation, pathogens deploy high-affinity metal acquisition systems, best exemplified by siderophores to acquire iron. Although pathogen strategies to resist the toxic effects of high Cu have been elucidated, the role of Cu starvation and the existence of Cu acquisition systems are less well characterized. In this study, we examined the role of diisonitrile chalkophores of pathogenic mycobacteria, synthesized by the enzymes encoded by the virulence-associated nrp gene cluster, in metal acquisition. nrp gene cluster expression is strongly induced by starvation or chelation of Cu but not starvation of Zn or excess Cu. Mycobacterium tuberculosis and Mycobacterium marinum strains lacking the nrp-encoded nonribosomal peptide sythetase, the fadD10 adenylate-forming enzyme, or the uncharacterized upstream gene ppe1 are all sensitized to Cu, but not Zn, starvation. This low Cu sensitivity is rescued by genetic complementation or by provision of a synthetic diisonitrile chalkophore. These data demonstrate that diisonitrile lipopeptides in mycobacteria are chalkophores that facilitate survival under Cu-limiting conditions and suggest that Cu starvation is a relevant stress for M. tuberculosis in the host.
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影响因子：
14.8
作者：
Chaturvedi, Kaveri S.;Hung, Chia S.;Crowley, Jan R.;Stapleton, Ann E.;Henderson, Jeffrey P.
通讯作者：
Henderson, Jeffrey P.
影响因子：
4.8
作者：
Bhatt K;Machado H;Osório NS;Sousa J;Cardoso F;Magalhães C;Chen B;Chen M;Kim J;Singh A;Ferreira CM;Castro AG;Torrado E;Jacobs WR Jr;Bhatt A;Saraiva M
通讯作者：
Saraiva M
影响因子：
30.3
作者：
Botella H;Peyron P;Levillain F;Poincloux R;Poquet Y;Brandli I;Wang C;Tailleux L;Tilleul S;Charrière GM;Waddell SJ;Foti M;Lugo-Villarino G;Gao Q;Maridonneau-Parini I;Butcher PD;Castagnoli PR;Gicquel B;de Chastellier C;Neyrolles O
通讯作者：
Neyrolles O
影响因子：
2.8
作者：
Bardarov, S;Bardarov, S;Jacobs, WR
通讯作者：
Jacobs, WR
DOI：
10.1073/pnas.1513447112
发表时间：
2015-09-22
影响因子：
11.1
作者：
Li, Cissy X.;Gleason, Julie E.;Culotta, Valeria Cizewski
通讯作者：
Culotta, Valeria Cizewski