MmpS4 promotes glycopeptidolipids biosynthesis and export in Mycobacterium smegmatis

Deshayes, Caroline; Bach, Horacio; Euphrasie, Daniel; Attarian, Rodgoun; Coureuil, Mathieu; Sougakoff, Wladimir; Laval, Françoise; Av‐Gay, Yossef; Daffé, Mamadou; Etienne, Gilles; Reyrat, Jean‐Marc

doi:10.1111/j.1365-2958.2010.07385.x

Cited by 66 publications

(69 citation statements)

References 51 publications

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“…For example, the inability to secrete the de novo synthesized siderophore, pyoverdine, a major virulence factor of P. aeruginosa, impairs its production (25). Likewise, MmpS4 connects biosynthesis enzymes for the synthesis of glycopeptidolipids, a major outer membrane lipid, with the transporter MmpL4 in M. smegmatis and, thus, couples biosynthesis and export (26). However, no interaction between the mycobactin biosynthesis enzyme G (MbtG) and MmpS4 was detected in crosslinking experiments in Mtb (14).…”

Section: Discussionmentioning

confidence: 99%

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Jones

Wells

Madduri

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

101

106

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Siderophores are small iron-binding molecules secreted by bacteria to scavenge iron. Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis, produces the siderophores mycobactin and carboxymycobactin. Complexes of the mycobacterial membrane proteins MmpS4 and MmpS5 with the transporters MmpL4 and MmpL5 are required for siderophore export and virulence in Mtb.Here we show that, surprisingly, mycobactin or carboxymycobactin did not rescue the low-iron growth defect of the export mutant but severely impaired growth. Exogenous siderophores were taken up by the export mutant, and siderophore-delivered iron was used, but the deferrated siderophores accumulated intracellularly, indicating a blockade of siderophore recycling. This hypothesis was confirmed by the observation that radiolabeled carboxymycobactin was taken up and secreted again by Mtb. Addition of iron salts to an Mtb siderophore biosynthesis mutant stimulated more growth in the presence of a limiting amount of siderophores than iron-loaded siderophores alone. Thus, recycling enables Mtb to acquire iron at lower metabolic cost because Mtb cannot use iron salts without siderophores. Exogenous siderophores were bactericidal for the export mutant in submicromolar quantities. High-resolution mass spectrometry revealed that endogenous carboxymycobactin also accumulated in the export mutant. Toxic siderophore accumulation is prevented by a drug that inhibits siderophore biosynthesis. Intracellular accumulation of siderophores was toxic despite the use of an alternative iron source such as hemin, suggesting an additional inhibitory mechanism independent of iron availability. This study indicates that targeting siderophore export/recycling would deliver a one-two punch to Mtb: restricting access to iron and causing toxic intracellular siderophore accumulation.

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Section: Discussionmentioning

confidence: 99%

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Jones

Wells

Madduri

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

101

106

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“…Deshayes et al (24) deleted mmpS4 in M. smegmatis, thereby causing a switch from smooth to rough morphology, although the mutant was still able to produce a small amount of a "GPL-like molecule." MALDI-TOF MS of the lipid extract from this mutant had a major peak 14 Da higher than that of the wild-type GPL.…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed 8 genes in the GPL locus, including the genes in which spontaneous insertions/deletions (indels) were previously identified in rough M. abscessus clinical strains (mps1 and mmpL4b) (22) as well as those which when experimentally rendered nonfunctional resulted in a switch from smooth to rough in M. abscessus or M. smegmatis (gap, mps2, mbtH, mmpL4b, and mmpS4) (17,(23)(24)(25). fmt and mmpL4a were included because of their adjacency to the above genes (Fig.…”

Section: Phylogenetic Analysis Of the Clinical Isolates By Mlstmentioning

confidence: 99%

Clonal Diversification and Changes in Lipid Traits and Colony Morphology in Mycobacterium abscessus Clinical Isolates

et al. 2015

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fThe smooth-to-rough colony morphology shift in Mycobacterium abscessus has been implicated in loss of glycopeptidolipid (GPL), increased pathogenicity, and clinical decline in cystic fibrosis (CF) patients. However, the evolutionary phenotypic and genetic changes remain obscure. Serial isolates from nine non-CF patients with persistent M. abscessus infection were characterized by colony morphology, lipid profile via thin-layer chromatography and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), sequencing of eight genes in the GPL locus, and expression level of fadD23, a key gene involved in the biosynthesis of complex lipids. All 50 isolates were typed as M. abscessus subspecies abscessus and were clonally related within each patient. Rough isolates, all lacking GPL, predominated at later disease stages, some showing variation within rough morphology. While most (77%) rough isolates harbored detrimental mutations in mps1 and mps2, 13% displayed previously unreported mutations in mmpL4a and mmpS4, the latter yielding a putative GPL precursor. Two isolates showed no deleterious mutations in any of the eight genes sequenced. Mixed populations harboring different GPL locus mutations were detected in 5 patients, demonstrating clonal diversification, which was likely overlooked by conventional acid-fast bacillus ( MABSC causes serious chronic pulmonary infections in those with underlying conditions such as bronchiectasis or cystic fibrosis (CF). In the United States and some other parts of the world, it is the second most frequent pulmonary nontuberculous mycobacterial (NTM) infection (28%), after Mycobacterium avium complex, and its prevalence is increasing (6, 7). MABSC causes significant mortality in the CF population. In Scandinavian countries, one-fourth of CF patients who have persistently positive MABSC sputum cultures have received lung transplantation or died (8).Glycopeptidolipid (GPL) is the most abundant glycolipid in the outer cell envelope of MABSC, and its synthesis and transport are controlled by the GPL locus (9). A growing number of studies have linked the rough colony morphology in MABSC to loss of GPL, increased pathogenicity, and clinical decline in CF patients (10)(11)(12)(13)(14)(15)(16). While most studies of persistent MABSC infection focused on CF patients, less is known about MABSC in the non-CF population regarding presence of mixed populations, clonal relatedness, and phenotypic and genotypic changes of strains collected over time.We have very limited understanding of the evolutionary phenotypic and genetic changes occurring in MABSC during persistent human lung infection. We lack the fundamental knowledge needed to identify selective pressures associated with rough morphology and, once identified, how to reverse them. To address these questions, we collected serial clinical isolates of M. abscessus from non-CF patients with persistent pulmonary infection who were followed for 5 years or more and assessed strain relatedness and diversity, colony...

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“…Five genes encoding MmpS proteins are adjacent to genes encoding MmpL proteins (8,13). Work in the model organism Mycobacterium smegmatis demonstrated that MmpS4 was required for bacterial sliding motility and biofilm formation (19). That the mmpS4 and mmpL4 mutants had similar phenotypes underscores a coordinated function for cognate MmpSMmpL proteins.…”

Section: Tuberculosis (Tb)mentioning

confidence: 99%

Crystal Structure of the Transcriptional Regulator Rv0678 of Mycobacterium tuberculosis

Radhakrishnan¹,

Kumar²,

Wright

et al. 2014

Journal of Biological Chemistry

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Background:The expression of the Mycobacterium tuberculosis MmpS5-MmpL5 transporter is controlled by the MarR-like transcriptional regulator Rv0678. Results: Rv0678 forms a dimeric two-domain molecule with the architecture similar to members of the MarR family of transcriptional regulators. Conclusion: Rv0678 is distinct in that its DNA-binding and dimerization domains cooperate to bind an inducing ligand. Significance: These findings suggest a mechanism for ligand and regulator derepression.

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MmpS4 promotes glycopeptidolipids biosynthesis and export in Mycobacterium smegmatis

Cited by 66 publications

References 51 publications

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

Clonal Diversification and Changes in Lipid Traits and Colony Morphology in Mycobacterium abscessus Clinical Isolates

Crystal Structure of the Transcriptional Regulator Rv0678 of Mycobacterium tuberculosis

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