Inhibitors of type III secretion in Yersinia: Design, synthesis and multivariate QSAR of 2-arylsulfonylamino-benzanilides

Kauppi, Anna M.; Andersson, C. David; Norberg, Henrik A.; Sundin, Charlotta; Linusson, Anna; Elofsson, Mikael

doi:10.1016/j.bmc.2007.07.047

Cited by 26 publications

(24 citation statements)

References 45 publications

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“…Initial experiments by the use of this method yielded 4 lead compounds from the screening of 9,400 compounds from the ChemBridge DiverSet F library. Initial structure-activity relationship studies (13,21,30) have been performed with two of these compounds, a salicylaldehyde compound (previously designated INP0007 [20]) and a 2-arylsulfonylamino-benzanilide, by using activity assays based on whole bacteria, because the targets of these compounds are not established. The activities of INP0007 and selected analogs against both Salmonella enterica serovar Typhimurium have been tested in vitro and in a tissue culture model (20,29), and the activities of these compounds against Chlamydia trachomatis have been tested in tissue culture (2,28).…”

Section: Discussionmentioning

confidence: 99%

Targeting Type III Secretion in Yersinia pestis

Pan

Brady

Leong

et al. 2009

Antimicrob Agents Chemother

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Yersinia pestis, the causative agent of plague, utilizes a plasmid-encoded type III secretion system (T3SS) to aid it with its resistance to host defenses. This system injects a set of effector proteins known as Yops (Yersinia outer proteins) into the cytosol of host cells that come into contact with the bacteria. T3SS is absolutely required for the virulence of Y. pestis, making it a potential target for new therapeutics. Using a novel and simple high-throughput screening method, we examined a diverse collection of chemical libraries for small molecules that inhibit type III secretion in Y. pestis. The primary screening of 70,966 compounds and mixtures yielded 421 presumptive inhibitors. We selected eight of these for further analysis in secondary assays. Four of the eight compounds effectively inhibited Yop secretion at micromolar concentrations. Interestingly, we observed differential inhibition among Yop species with some compounds. The compounds did not inhibit bacterial growth at the concentrations used in the inhibition assays. Three compounds protected HeLa cells from type III secretion-dependent cytotoxicity. Of the eight compounds examined in secondary assays, four show good promise as leads for structure-activity relationship studies. They are a diverse group, with each having a chemical scaffold not only distinct from each other but also distinct from previously described candidate type III secretion inhibitors.

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Section: Discussionmentioning

confidence: 99%

Targeting Type III Secretion in Yersinia pestis

Pan

Brady

Leong

et al. 2009

Antimicrob Agents Chemother

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“…Most prominent among these is the development of small molecule inhibitors of type III secretion (T3S) (11,23,24,32,33). These inhibitors have been identified using whole-cell screens to detect functional inhibition of T3S.…”

Section: Identification Of Small Molecule Inhibitors Of Lcrfmentioning

confidence: 99%

Small Molecule Inhibitors of LcrF, a Yersinia pseudotuberculosis Transcription Factor, Attenuate Virulence and Limit Infection in a Murine Pneumonia Model

et al. 2010

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“…2, compound 3) identified in their original screen and were able to improve inhibitory activity from 68% to 91% (35). Similar studies on salicylanilides and salicylidene acylhydrazides showed strong correlations between theoretical QSAR models and experimental T3SS inhibition (17,18).…”

Section: Structure-activity Relationship Studiesmentioning

confidence: 71%

Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Duncan

Linington

Auerbuch

2012

Antimicrob Agents Chemother

102

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The recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by "magic bullet" drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

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Inhibitors of type III secretion in Yersinia: Design, synthesis and multivariate QSAR of 2-arylsulfonylamino-benzanilides

Cited by 26 publications

References 45 publications

Targeting Type III Secretion in Yersinia pestis

Targeting Type III Secretion in Yersinia pestis

Small Molecule Inhibitors of LcrF, a Yersinia pseudotuberculosis Transcription Factor, Attenuate Virulence and Limit Infection in a Murine Pneumonia Model

Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

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