MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance

Peterson, Eliza J.R.; Brooks, Aaron N.; Reiss, David J; Kaur, Amardeep; Do, Julie; Pan, Min; Wu, Wei-Ju; Morrison, Robert; Srinivas, Vivek; Carter, Warren; Arrieta-Ortiz, Mario L.; Ruiz, Rene A.; Bhatt, Apoorva; Baliga, Nitin S.

doi:10.1016/j.celrep.2023.112875

Cited by 13 publications

(8 citation statements)

References 110 publications

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“…7). Conversely, in Mtb, mtrA knockdown renders Mtb more susceptible to drugs tested with molecular weights above 200 g/mol; however, but there is no change in sensitivity to the translation inhibitor LZD[18, 33]. This indicates a distinctive influence of the MtrAB TCS on drug resistance mechanisms between these mycobacterial species.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in Streptomyces coelicolor, it plays an important role in the developmental life cycle [16]. Additionally, in Mtb, MtrAB is an essential TCS involved in cell replication and division [18,19]. Furthermore, MtrAB has been reported to be involved in drug resistance.…”

Section: Introductionmentioning

confidence: 99%

“…The absence of mtrAB in Corynebacterium glutamicum leads to heightened susceptibility to penicillin and vancomycin (VAN), a phenomenon analogous to the increased sensitivity observed upon the deletion of mtrB in Mycobacterium avium [14,20]. Comparably, in both Mtb and Mycobacterium smegmatis (Msm), the knockdown and knockout of mtrA, respectively, resulted in altered sensitivity to various drugs [18,21]. However, in-depth studies of Mab TCS, particularly the MtrAB, have not been performed.…”

Section: Introductionmentioning

confidence: 99%

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MtrAB two-component system is crucial for the intrinsic resistance and virulence ofMycobacterium abscessus

Zhang,

Ju,

et al. 2024

Preprint

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Mycobacterium abscessus (Mab) poses serious therapeutic challenges, principally due to its intrinsic resistance to a wide array of antibiotics. The pressing issue of drug resistance has spurred an urgent need to explore novel targets and develop new therapeutic agents against Mab. The MtrAB two-component system, conserved among Actinobacteria, is pivotal for regulating various metabolic processes. Nevertheless, the role of MtrAB in Mab remains elusive. In this study, we uncovered that Mab strains with disrupted mtrA, mtrB or both exhibited heightened susceptibility to a variety of antibiotics with diverse mechanisms of action, in contrast to the wild-type strain. In a murine model, rifabutin, bedaquiline, and amikacin, which were inactive against the wild-type Mab strain, demonstrated efficacy against all the mtrA, mtrB and mtrAB knockout strains, significantly reducing pulmonary bacterial burdens compared to vehicle controls after ten days of treatment. Notably, the virulence of all the mtrA, mtrB, and mtrAB knockout strains was highly diminished in the murine model, as evidenced by a substantial decrease in bacterial load in the lungs of mice after 16 days. We observed that all three knockout strains exhibited a significantly reduced growth rate compared to the wild-type strain. We discovered that cells lacking mtrA, mtrB or both exhibited an elongated cell length and had multiple septa, suggesting that both MtrA and MtrB regulate cell division of Mab. Subsequently, an ethidium bromide accumulation assay disclosed that the absence of either mtrA or mtrB or both significantly increased cell envelope permeability. In summary, this study suggests that mtrA and mtrB play an important role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MtrAB two-component system is crucial for the intrinsic resistance and virulence ofMycobacterium abscessus

Zhang,

Ju,

et al. 2024

Preprint

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“…Most changes observed in BCGΔBCG1419c were reduced transcription, including that of genes belonging to the MtrA regulon (Table 1). Among the known functions of the MtrA regulon, we recently reported that it modulates cell division and intrinsic tolerance and drug resistance 21 . Within this regulon, pirG (exported repetitive protein precursor, erp 22 ) has been described as required for virulence, whereas BCG_1539 (hypothetical invasion protein, ripA 23 ) is required for peptidoglycan cleavage and virulence, BCG_1540 (hypothetical invasion protein, ripB 24 ) is also required for peptidoglycan remodeling.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the transcriptome, lipidome, and c-di-GMP production between BCGΔBCG1419c and BCG, with Mincle- and Myd88-dependent induction of proinflammatory cytokines in murine macrophages

Flores-Valdez,

Peterson,

Aceves-Sánchez

et al. 2024

Sci Rep

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We have previously reported the transcriptomic and lipidomic profile of the first-generation, hygromycin-resistant (HygR) version of the BCGΔBCG1419c vaccine candidate, under biofilm conditions. We recently constructed and characterized the efficacy, safety, whole genome sequence, and proteomic profile of a second-generation version of BCGΔBCG1419c, a strain lacking the BCG1419c gene and devoid of antibiotic markers. Here, we compared the antibiotic-less BCGΔBCG1419c with BCG. We assessed their colonial and ultrastructural morphology, biofilm, c-di-GMP production in vitro, as well as their transcriptomic and lipidomic profiles, including their capacity to activate macrophages via Mincle and Myd88. Our results show that BCGΔBCG1419c colonial and ultrastructural morphology, c-di-GMP, and biofilm production differed from parental BCG, whereas we found no significant changes in its lipidomic profile either in biofilm or planktonic growth conditions. Transcriptomic profiling suggests changes in BCGΔBCG1419c cell wall and showed reduced transcription of some members of the DosR, MtrA, and ArgR regulons. Finally, induction of TNF-α, IL-6 or G-CSF by bone-marrow derived macrophages infected with either BCGΔBCG1419c or BCG required Mincle and Myd88. Our results confirm that some differences already found to occur in HygR BCGΔBCG1419c compared with BCG are maintained in the antibiotic-less version of this vaccine candidate except changes in production of PDIM. Comparison with previous characterizations conducted by OMICs show that some differences observed in BCGΔBCG1419c compared with BCG are maintained whereas others are dependent on the growth condition employed to culture them.

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“…MtrA not only controls cell division [26] and cell wall metabolism, but also affects the susceptibility of Mtb to first-line anti-TB drugs [26] . Thus, MtrA is a key target for antimicrobial drugs [27] , [28] . Another TCS, PhoP/R, regulates the expression of more than 100 genes of Mtb [29] .…”

Section: Introductionmentioning

confidence: 99%

Structure-guided identification and characterization of potent inhibitors targeting PhoP and MtrA to combat mycobacteria

Su,

Lai,

Tsai

et al. 2024

Computational and Structural Biotechnology Journal

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MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance

Cited by 13 publications

References 110 publications

MtrAB two-component system is crucial for the intrinsic resistance and virulence ofMycobacterium abscessus

MtrAB two-component system is crucial for the intrinsic resistance and virulence ofMycobacterium abscessus

Comparison of the transcriptome, lipidome, and c-di-GMP production between BCGΔBCG1419c and BCG, with Mincle- and Myd88-dependent induction of proinflammatory cytokines in murine macrophages

Structure-guided identification and characterization of potent inhibitors targeting PhoP and MtrA to combat mycobacteria

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