<i>Mycobacterium tuberculosis metC</i>(Rv3340) derived hydrogen sulphide conferring bacteria stress survival

Lambert, Nzungize; Ali, Kaisar; Wang, Xiaoyu; Huang, Xue; Yang, Wenmin; Duan, Xiangke; Yan, Shiyu; Li, Chunyan; Abdalla, Abualgasim Elgaili; Jeyakkumar, Ponmani; Xie, Jianping

doi:10.1080/1061186x.2019.1579820

Cited by 16 publications

(8 citation statements)

References 60 publications

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“…Virtually all bacteria generate H 2 S via enzymes orthologous to the mammalian cystathionine g-lyase (CSE), cystathionine b-synthase (CBS), or 3-mercaptopyruvate sulfurtransferase (21)(22)(23)(24). Genetic disruption of H 2 S biogenesis sensitizes a wide range of pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa, to different classes of bactericidal drugs and to the host immune response (23,(25)(26)(27).…”

mentioning

confidence: 99%

Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance

Shatalin

Nuthanakanti

Kaushik

et al. 2021

Science

149

130

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Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)–mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

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mentioning

confidence: 99%

Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance

Shatalin

Nuthanakanti

Kaushik

et al. 2021

Science

149

130

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“…To examine whether MtLysX2 has unique functional roles given its unprecedented topology, we introduced a replicative plasmid bearing the Mtb lysX2 gene and its putative native promoter into M. smegmatis strain mc 2 155. This strain has been successfully used as surrogate of Mtb [32][33][34][35][36], and does not encode endogenous MtLysX2. The plasmid we used is based on the replicon of pAL5000, which has an estimated copy number of three in M. smegmatis [37] theoretically guaranteeing a protein expression level close to the physiological expression occurring in M. tuberculosis.…”

Section: Heterologous Expression Of Mtlysx2 In M Smegmatismentioning

confidence: 99%

LysX2 is a Mycobacterium tuberculosis membrane protein with an extracytoplasmic MprF-like domain

et al. 2022

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Background Aminoacyl-phosphatidylglycerol (aaPG) synthases are bacterial enzymes that usually catalyze transfer of aminoacyl residues to the plasma membrane phospholipid phosphatidylglycerol (PG). The result is introduction of positive charges onto the cytoplasmic membrane, yielding reduced affinity towards cationic antimicrobial peptides, and increased resistance to acidic environments. Therefore, these enzymes represent an important defense mechanism for many pathogens, including Staphylococcus aureus and Mycobacterium tuberculosis (Mtb), which are known to encode for lysyl-(Lys)-PG synthase MprF and LysX, respectively. Here, we used a combination of bioinformatic, genetic and bacteriological methods to characterize a protein encoded by the Mtb genome, Rv1619, carrying a domain with high similarity to MprF-like domains, suggesting that this protein could be a new aaPG synthase family member. However, unlike homologous domains of MprF and LysX that are positioned in the cytoplasm, we predicted that the MprF-like domain in LysX2 is in the extracytoplasmic region. Results Using genetic fusions to the Escherichia coli proteins PhoA and LacZ of LysX2, we confirmed this unique membrane topology, as well as LysX and MprF as benchmarks. Expression of lysX2 in Mycobacterium smegmatis increased cell resistance to human β-defensin 2 and sodium nitrite, enhanced cell viability and delayed biofilm formation in acidic pH environment. Remarkably, MtLysX2 significantly reduced the negative charge on the bacterial surface upon exposure to an acidic environment. Additionally, we found LysX2 orthologues in major human pathogens and in rapid-growing mycobacteria frequently associated with human infections, but not in environmental and non-pathogenic mycobacteria. Conclusions Overall, our data suggest that LysX2 is a prototype of a new class within the MprF-like protein family that likely enhances survival of the pathogenic species through its catalytic domain which is exposed to the extracytoplasmic side of the cell membrane and is required to decrease the negative charge on the bacterial surface through a yet uncharacterized mechanism.

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“…Moreover, the M. tuberculosis homocysteine synthase MetC (Rv3340), a key enzyme of the methionine synthesis pathway, was hypothesized to promote STR resistance. Indeed, overexpression of metC in an M. smegmatis mutant was shown to mediate STR resistance [ 66 ]. The transcriptional regulator whiB7 was also involved in mechanisms of aminoglycoside resistance, including STR [ 67 ].…”

Section: Emergence Of Streptomycin-resistant Strainsmentioning

confidence: 99%

The Neglected Contribution of Streptomycin to the Tuberculosis Drug Resistance Problem

Rocha

Viveiros²,

Saraiva

et al. 2021

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The airborne pathogen Mycobacterium tuberculosis is responsible for a present major public health problem worsened by the emergence of drug resistance. M. tuberculosis has acquired and developed streptomycin (STR) resistance mechanisms that have been maintained and transmitted in the population over the last decades. Indeed, STR resistant mutations are frequently identified across the main M. tuberculosis lineages that cause tuberculosis outbreaks worldwide. The spread of STR resistance is likely related to the low impact of the most frequent underlying mutations on the fitness of the bacteria. The withdrawal of STR from the first-line treatment of tuberculosis potentially lowered the importance of studying STR resistance. However, the prevalence of STR resistance remains very high, could be underestimated by current genotypic methods, and was found in outbreaks of multi-drug (MDR) and extensively drug (XDR) strains in different geographic regions. Therefore, the contribution of STR resistance to the problem of tuberculosis drug resistance should not be neglected. Here, we review the impact of STR resistance and detail well-known and novel candidate STR resistance mechanisms, genes, and mutations. In addition, we aim to provide insights into the possible role of STR resistance in the development of multi-drug resistant tuberculosis.

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Mycobacterium tuberculosis metC(Rv3340) derived hydrogen sulphide conferring bacteria stress survival

Cited by 16 publications

References 60 publications

Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance

Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance

LysX2 is a Mycobacterium tuberculosis membrane protein with an extracytoplasmic MprF-like domain

The Neglected Contribution of Streptomycin to the Tuberculosis Drug Resistance Problem

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Mycobacterium tuberculosis metC(Rv3340) derived hydrogen sulphide conferring bacteria stress survival

Cited by 16 publications

References 60 publications

Inhibitors of bacterial H 2 S biogenesis targeting antibiotic resistance and tolerance

Inhibitors of bacterial H 2 S biogenesis targeting antibiotic resistance and tolerance

LysX2 is a Mycobacterium tuberculosis membrane protein with an extracytoplasmic MprF-like domain

The Neglected Contribution of Streptomycin to the Tuberculosis Drug Resistance Problem

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Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance

Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance