Down-regulation of malate synthase in Mycobacterium tuberculosis H37Ra leads to reduced stress tolerance, persistence and survival in macrophages

Singh, Kumar Sachin; Sharma, Rolee; Keshari, Deepa; Singh, Nirbhay Kumar; Singh, S. N.

doi:10.1016/j.tube.2017.07.006

Cited by 20 publications

(11 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, Staphylococcus aureus, a facultative intracellular pathogen, alters its central carbon metabolism to promote its survival in the phagosome (60,61). The ability to utilize short-chain fatty acids is required for full virulence of Campylobacter jejuni (62), and Mycobacterium tuberculosis requires the glyoxylate shunt for survival in macrophages and mice (63,64). Here, we show that, similarly to many other pathogens, C. albicans appropriately responds to multiple alternative carbon sources to gain advantages over the host.…”

Section: Discussionmentioning

confidence: 99%

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

Williams

Lorenz

2020

mBio

View full text Add to dashboard Cite

The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of the phagocyte. C. albicans rapidly adapts to the phagosome by upregulating multiple alternative carbon utilization pathways, particularly those for amino acids, carboxylic acids, and N-acetylglucosamine (GlcNAc). Here, we report that C. albicans recognizes these carbon sources both as crucial nutrients and as independent signals in its environment. Even in the presence of glucose, each carbon source promotes increased resistance to a unique profile of stressors; lactate promotes increased resistance to osmotic and cell wall stresses, amino acids increased resistance to oxidative and nitrosative stresses, and GlcNAc increased resistance to oxidative stress and caspofungin, while all three alternative carbon sources have been shown to induce resistance to fluconazole. Moreover, we show mutants incapable of utilizing these carbon sources, in particular, strains engineered to be defective in all three pathways, are significantly attenuated in both macrophage and mouse models, with additive effects observed as multiple carbon pathways are eliminated, suggesting that C. albicans simultaneously utilizes multiple carbon sources within the macrophage phagosome and during disseminated candidiasis. Taking the data together, we propose that, in addition to providing energy to the pathogen within host environments, alternative carbon sources serve as niche-specific priming signals that allow C. albicans to recognize microenvironments within the host and to prepare for stresses associated with that niche, thus promoting host adaptation and virulence. IMPORTANCE Candida albicans is a fungal pathogen and a significant cause of morbidity and mortality, particularly in people with defects, sometimes minor ones, in innate immunity. The phagocytes of the innate immune system, particularly macrophages and neutrophils, generally restrict this organism to its normal commensal niches, but C. albicans shows a robust and multifaceted response to these cell types. Inside macrophages, a key component of this response is the activation of multiple pathways for the utilization of alternative carbon sources, particularly amino acids, carboxylic acids, and N-acetylglucosamine. These carbon sources are key sources of energy and biomass but also independently promote stress resistance, induce cell wall alterations, and affect C. albicans interactions with macrophages. Engineered strains incapable of utilizing these alternative carbon pathways are attenuated in infection models. These data suggest that C. albicans recognizes nutrient composition as an indicator of specific host environments and tailors its responses accordingly.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

Williams

Lorenz

2020

mBio

View full text Add to dashboard Cite

show abstract

“…The investigation of novel pharmacological targets, such as InhA, MmpL3, DprE1 and QcrB, plays a fundamental role in the development of new potential antitubercular agents [4]. Since the most promising targets are membrane proteins, the identified hit compounds may also interfere with the integrity of the host membranes; therefore, the selection of different targets to be tackled is still urgent [5][6][7][8]. In addition, there are a number of novel anti-TB compounds in clinical trial, and two new drugs have been recently approved: delamanid and bedaquiline.…”

Section: Introductionmentioning

confidence: 99%

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

Chiarelli

Mori

Barlocco

et al. 2018

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (K = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.

show abstract

“…Disruption of the TCA cycle, especially alternate catabolism through the glyoxylate shunt, has been linked to antibiotic tolerance in multiple bacterial species, including P. aeruginosa (64), S. aureus (65,66), and S. epidermis (67), suggesting that this pathway may be a common mechanism for promoting antibiotic tolerance. In M. tuberculosis , downregulation of the malate synthase GlcB, one of the enzymes in the glyoxylate shunt, caused increased susceptibility to both rifampin and to nitrosative and oxidative stresses in vitro (68). Deficiency of isocitrate lyase, another glyoxylate shunt enzyme, also led to increased susceptibility of M. tuberculosis to antibiotics in vitro (69) and decreased survival in activated macrophages and mice (27).…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of intrinsic antibiotic tolerance inMycobacterium avium

Matern

Parker

Danchik

et al. 2021

Preprint

View full text Add to dashboard Cite

Mycobacterium avium complex (MAC) is one of the most prevalent causes of nontuberculous mycobacteria pulmonary infection in the United States, yet it remains understudied. Current MAC treatment requires more than a year of intermittent to daily combination antibiotic therapy, depending on disease severity. In order to shorten and simplify curative regimens, it is important to identify the innate bacterial factors contributing to reduced antibiotic susceptibility, namely antibiotic tolerance genes. In this study, we performed a genome-wide transposon screen to elucidate M. avium genes that play a role in the bacterium’s tolerance to first- and second-line antibiotics. We identified a total of 193 unique M. avium mutants with significantly altered susceptibility to at least one of the four clinically used antibiotics we tested, including two mutants (in DFS55_00905 and DFS55_12730) with panhypersusceptibility. The products of the antibiotic tolerance genes we have identified may represent novel targets for future drug development studies aimed at shortening the duration of therapy for MAC infections.

show abstract

Down-regulation of malate synthase in Mycobacterium tuberculosis H37Ra leads to reduced stress tolerance, persistence and survival in macrophages

Cited by 20 publications

References 38 publications

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

Genetic determinants of intrinsic antibiotic tolerance inMycobacterium avium

Contact Info

Product

Resources

About