Salicylate uniquely induces a 27-kDa protein in tubercle bacillus

Sun, Zhonghe; Cheng, Shao Ji; Zhang, Hao; Zhang, Ying

doi:10.1111/j.1574-6968.2001.tb10843.x

Cited by 22 publications

(27 citation statements)

References 18 publications

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“…The following effects have been noted: reduction of adhesion to relevant biomatrices (29), reduction of capsule production (30), mitigation of biofilm formation (31), and diminution of vegetation growth, intravegetation bacterial proliferation, and hematogenous dissemination in experimental infective endocarditis (32). Salicylic acid also has been shown to upregulate the translation of specific gene loci, including multiple antibiotic-resistance loci (33); to induce cytoplasmic proteins (34); and to increase quinolone resistance (35). We recently studied the potential antimicrobial mechanisms of aspirin in the infective endocarditis model (8) and demonstrated that salicylic acid was the principal mediator of these antimicrobial effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

Kupferwasser

Yeaman²,

Nast³

et al. 2003

J. Clin. Invest.

110

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Aspirin has been previously shown to reduce the in vivo virulence of Staphylococcus aureus in experimental endocarditis, through antiplatelet and antimicrobial mechanisms. In the present study, salicylic acid, the major in vivo metabolite of aspirin, mitigated two important virulence phenotypes in both clinical and laboratory S. aureus strains: α-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the α-hemolysin gene promoter, hla, and the fibronectin gene promoter, fnbA. Transcriptional analysis, fluorometry, and flow cytometry revealed evidence of salicylic acid-mediated activation of the stress-response gene sigB. Expression of the sigBrepressible global regulon sarA and the global regulon agr were also mitigated by salicylic acid, corresponding to the reduced expression of the hla and fnbA genes in vitro. Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo. Therefore, aspirin has the potential to be an adjuvant therapeutic agent against endovascular infections that result from S. aureus, by downmodulating key staphylococcal global regulons and structural genes in vivo, thus abrogating relevant virulence phenotypes.

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Section: Discussionmentioning

confidence: 99%

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

Kupferwasser

Yeaman²,

Nast³

et al. 2003

J. Clin. Invest.

110

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“…Rv0560c has been shown to be induced by salicylate (Sun et al, 2001), a compound that also increases oxygen consumption when added to M. tuberculosis cultures (Bernheim, 1940), and is clustered with other genes involved in ubiquinone biosynthesis (Sun et al, 2001). The function of Rv3866 is not known, but it is located just upstream of the virulence-associated RD1 element on the M. tuberculosis chromosome (Sassetti & Rubin, 2003).…”

Section: Cell Wallmentioning

confidence: 99%

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions

Starck

Källenius

Marklund³

et al. 2004

Microbiology

135

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Data are presented from two-dimensional (2-D) PAGE analysis of Mycobacterium tuberculosis strain Harlingen grown during aerobic and anaerobic culture, according to a modified Wayne dormancy model. M. tuberculosis cultures were grown to the transition point between exponential growth and stationary phase in the presence of oxygen (7 days) and then part of the cultures was shifted to anaerobic conditions for 16 days. Growth declined similarly during aerobic and anaerobic conditions, whereas the ATP consumption rapidly decreased in the anaerobic cultures. 2-D PAGE revealed 50 protein spots that were either unique to, or more abundant during, anaerobic conditions and 16 of these were identified by MALDI-TOF. These proteins were the a-crystalline homologue (HspX), elongation factor Tu (Tuf), GroEL2, succinyl-CoA : 3-oxoacid-CoA transferase (ScoB), mycolic acid synthase (CmaA2), thioredoxin (TrxB2), b-ketoacyl-ACP synthase (KasB), L-alanine dehydrogenase (Ald), Rv2005c, Rv2629, Rv0560c, Rv2185c and Rv3866. Some protein spots were found to be proteolytic fragments, e.g. HspX and GroEL2. These data suggest that M. tuberculosis induces expression of about 1 % of its genes in response to dormancy. INTRODUCTIONHuman tuberculosis (TB) is caused by an intracellular pathogen, Mycobacterium tuberculosis, which causes both latent and acute illness. Approximately eight million active cases are reported annually with 2 million deaths. In addition, about one-third of the global population is estimated to suffer from latent tuberculosis (Dye et al., 1999), which can be reactivated even after several decades. The fact that the bacilli can shift into a dormant state is of therapeutic importance, since this dormant state induces resistance to the two most important TB-drugs, rifampicin and isoniazide (Wayne & Sramek, 1994). One of the most challenging problems in TB research is to reveal the mechanisms behind latency.Latency is believed to involve a non-replicating persistence of mycobacteria or a very slow growth. One important condition believed to contribute to latency is reduced access to oxygen. M. tuberculosis is generally regarded as a strictly aerobic bacillus, although it can survive for a long time in a micro-aerophilic environment as long as the shift is not too abrupt (Wayne & Hayes, 1996). An in vitro model to study this persistent state is the so-called Wayne dormancy model, in which the bacteria downregulate their metabolism due to reduced access to oxygen (Wayne & Hayes, 1996). Another dormancy model utilizes nutrient starvation to induce a state where M. tuberculosis arrests growth and decreases its respiration rate (Betts et al., 2002). Recently it was demonstrated that inhibition of respiration by nitric oxide might induce a dormant state in M. tuberculosis . One should recognize, however, that the evidence linking in vitro dormant states of M. tuberculosis to human latent infection still remains circumstantial.The vaccine strain Mycobacterium bovis BCG has been reported to occasionally persist in a latent state in ...

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“…Studies with cultured bacilli implicate PAS efflux via TAP as a potential resistance mechanism (121), yet a role for TAP in the limitation of PAS efficacy has yet to be established in infection models or in a clinical setting. Further, a PAS inactivation pathway involving the uncharacterized SAMdependent methyltransferase Rv0560c has been suggested (34,109,124,125) and may be the basis for methionine-linked antag- onism of PAS activity (81,82). Yet, whether this pathway limits the full potential action of PAS remains to be demonstrated.…”

Section: Closing Remarksmentioning

confidence: 99%

Mycobacterium tuberculosis Folate Metabolism and the Mechanistic Basis for para -Aminosalicylic Acid Susceptibility and Resistance

Minato

Thiede

Kordus

et al. 2015

Antimicrob Agents Chemother

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b para-Aminosalicylic acid (PAS) entered clinical use in 1946 as the second exclusive drug for the treatment of tuberculosis (TB). While PAS was initially a first-line TB drug, the introduction of more potent antitubercular agents relegated PAS to the secondline tier of agents used for the treatment of drug-resistant Mycobacterium tuberculosis infections. Despite the long history of PAS usage, an understanding of the molecular and biochemical mechanisms governing the susceptibility and resistance of M. tuberculosis to this drug has lagged behind that of most other TB drugs. Herein, we discuss previous studies that demonstrate PAS-mediated disruption of iron acquisition, as well as recent genetic, biochemical, and metabolomic studies that have revealed that PAS is a prodrug that ultimately corrupts one-carbon metabolism through inhibition of the formation of reduced folate species. We also discuss findings from laboratory and clinical isolates that link alterations in folate metabolism to PAS resistance. These advancements in our understanding of the basis of the susceptibility and resistance of M. tuberculosis to PAS will enable the development of novel strategies to revitalize this and other antimicrobial agents for use in the global effort to eradicate TB. Mycobacterium tuberculosis is responsible for approximately 8.6 million new cases of active tuberculosis (TB) infection and 1.3 million deaths annually despite the existence of TB therapy (1). While this therapy has a high success rate in curing drugsusceptible TB infections, it is challenging, in part because it requires a minimum of 6 months of treatment with drugs that are associated with adverse reactions (2, 3). These factors contribute to treatment errors and noncompliance, which have been implicated in the emergence of drug-resistant strains of M. tuberculosis (4, 5). Further, subsequent relapse of the disease can occur and is associated with a high incidence of drug resistance (6). Together, these complications have enabled the emergent spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis that require greater than 2 years of therapy with second-line drugs and threaten the efficacy of existing TB therapy (1, 7). Elucidating the mechanisms that govern the susceptibility and resistance of M. tuberculosis to existing antitubercular agents will facilitate the discovery of new therapeutic approaches to shorten treatment times and counter drug-resistant TB.para-Aminosalicylic acid (PAS) entered clinical use as a bacteriostatic antitubercular agent in 1946 (8). Shortly before the introduction of PAS, the discovery of streptomycin as a therapeutic tool had dramatically improved TB survival rates (9). At that time, it was apparent that the rapid emergence of streptomycin-resistant M. tuberculosis strains posed a threat to this monotherapy strategy for TB infection (9). As PAS was effective against streptomycinresistant strains of M. tuberculosis (10), it was soon recognized that combination therapy could reduce th...

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Salicylate uniquely induces a 27-kDa protein in tubercle bacillus

Cited by 22 publications

References 18 publications

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions

Mycobacterium tuberculosis Folate Metabolism and the Mechanistic Basis for para -Aminosalicylic Acid Susceptibility and Resistance

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