Substituted Salicylanilides as Inhibitors of Two-Component Regulatory Systems in Bacteria

Macielag, Mark J.; Demers, James P.; Fraga-Spano, Stephanie A.; Hlasta, Dennis J.; Johnson, Sigmond G.; Kanojia, Ramesh M.; Russell, Ronald K.; Sui, Zhihua; Weidner‐Wells, Michele A.; Werblood, Harvey M.; Foleno, Barbara D.; Goldschmidt, Raúl; Loeloff, Michael J.; Webb, Glenda C.; Barrett, John

doi:10.1021/jm9803572

Cited by 124 publications

(89 citation statements)

References 20 publications

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“…We observed that, in agreement with recent reports by Rajamuthiah et al (13), niclosamide showed strong antimicrobial activity against planktonic S. aureus with an IC 50 of 1.2 M. Furthermore, closantel, a homologue of niclosamide, also showed significant antimicrobial activity against planktonic S. aureus with an IC 50 below the lowest concentration tested (0.6 M), in agreement with the findings of Macielag et al (14).…”

Section: Resultssupporting

confidence: 93%

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Torres

Abercrombie

Srinivasan

et al. 2016

Antimicrob Agents Chemother

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It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 M, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus. We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies.

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Section: Resultssupporting

confidence: 93%

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Torres

Abercrombie

Srinivasan

et al. 2016

Antimicrob Agents Chemother

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“…Indeed, compounds that inhibit signal transduction through these systems have been shown to be effective even against multi-drug-resistant pathogens, including methicillin-resistant S. aureus and vancomycin-resistant Enterococcus faecium (2,20). The data presented here suggest that manipulation of SrrA-SrrB in S. aureus may suppress production of exotoxins.…”

Section: Vol 183 2001mentioning

confidence: 78%

Identification of a Novel Two-Component Regulatory System That Acts in Global Regulation of Virulence Factors ofStaphylococcus aureus

2001

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We have previously demonstrated that the presence of oxygen is necessary for the production of toxic shock syndrome toxin 1 (TSST-1) by Staphylococcus aureus in vitro. To investigate the mechanism by which oxygen might regulate toxin production, we identified homologs in S. aureus of the Bacillus subtilis resDE genes. The two-component regulatory system encoded by resDE, ResD-ResE, has been implicated in the global regulation of aerobic and anaerobic respiratory metabolism in B. subtilis. We have designated the S. aureus homologs srrAB (staphylococcal respiratory response). The effects of srrAB expression on expression of RNAIII (the effector molecule of the agr locus) and on production of TSST-1 (an exotoxin) and protein A (a surfaceassociated virulence factor) were investigated. Expression of RNAIII was inversely related to expression of srrAB. Disruption of srrB resulted in increased levels of RNAIII, while expression of srrAB in trans on a multicopy plasmid resulted in repression of RNAIII transcription, particularly in microaerobic conditions. Disruption of srrB resulted in decreased production of TSST-1 under microaerobic conditions and, to a lesser extent, under aerobic conditions as well. Overexpression of srrAB resulted in nearly complete repression of TSST-1 production in both microaerobic and aerobic conditions. Protein A production by the srrB mutant was upregulated in microaerobic conditions and decreased in aerobic conditions. Protein A production was restored to nearly wild-type levels by complementation of srrAB into the null mutant. These results indicate that the putative two-component system encoded by srrAB, SrrA-SrrB, acts in the global regulation of staphylococcal virulence factors, and may repress virulence factors under low-oxygen conditions. Furthermore, srrAB may provide a mechanistic link between respiratory metabolism, environmental signals, and regulation of virulence factors in S. aureus.Staphylococcus aureus is a leading cause of nosocomial infections worldwide (reviewed in reference 34). It is responsible for several serious diseases, including toxic shock syndrome (TSS), osteomyelitis, endocarditis, pneumonia, and septicemia, which are induced through the elaboration of a wide array of virulence factors. Numerous environmental signals have been demonstrated to act in the regulation of these virulence factors (reviewed in reference 25). Recognition of these signals likely enables S. aureus to sense appropriate host environments for coordinate expression of virulence factors. Several studies have shown that elevated oxygen, carbon dioxide, and protein levels, along with a relatively neutral pH, are required for exotoxin production by S. aureus (18,28,30,39,40). Todd et al. (35) showed that altering any of these conditions greatly reduced the synthesis of TSS toxin 1 (TSST-1) by S. aureus in vitro, and furthermore, material removed from sequestered focal infections with S. aureus contained similar components. It has also been demonstrated that insertion of a tampon raises vaginal ...

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“…Histidine kinase is the focus for the specific inhibition of two component signal transduction system in mycobacteria (95)(96)(97)(98). Based on this signal transduction system, a series of antimycobacterial salicylanilides and related compounds have been reported (99)(100)(101)(102). Inhibition of this type of regulation has been involved in the virulence of M. tuberculosis in mice (103).…”

Section: 24-benzothiadiazinesmentioning

confidence: 99%

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

et al. 2008

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Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.

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Substituted Salicylanilides as Inhibitors of Two-Component Regulatory Systems in Bacteria

Cited by 124 publications

References 20 publications

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Identification of a Novel Two-Component Regulatory System That Acts in Global Regulation of Virulence Factors ofStaphylococcus aureus

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

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