Development of improved inhibitors of wall teichoic acid biosynthesis with potent activity against Staphylococcus aureus

Lee, Kyung-Ae; Campbell, Jennifer; Swoboda, Jonathan G.; Cuny, Gregory D.; Walker, Suzanne

doi:10.1016/j.bmcl.2010.01.036

Cited by 63 publications

(58 citation statements)

References 12 publications

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“…Although little is known about the exact ratio of mutant populations in the targocil-resistant bacteria, the adhesion ability of mixed populations of mutant bacteria was also decreased. Although the mutation frequency of S. aureus for targocil resistance is higher than most antibiotics (23), this is most likely due to the fact that two classes of mutations can relieve the inhibitory effects of targocil. This study shows that once WTA-null mutants such as tarO and tarA mutants appear, they have limited ability to attach to or invade epithelial cells.…”

Section: Discussionmentioning

confidence: 98%

“…The WTA biosynthesis pathway constitutes a novel target for small-molecule inhibitors, and two inhibitory compounds have recently been reported (23,36). WTAs are phosphaterich, highly anionic polymers that are covalently linked to the peptidoglycan cell wall of most Gram-positive pathogens.…”

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confidence: 99%

“…This compound inhibits the growth of select S. aureus strains, including MRSA (36). A structureactivity relationship study of 1835F03 led to the discovery of an analog, targocil, that is 10-fold more potent (23) (Fig. 1).…”

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confidence: 99%

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In Vitro Antimicrobial Activity of Wall Teichoic Acid Biosynthesis Inhibitors against Staphylococcus aureus Isolates

Suzuki

Swoboda

Campbell

et al. 2011

Antimicrob Agents Chemother

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Staphylococcus aureus is the leading cause of invasive and superficial human infections, is increasingly antibiotic resistant, and is therefore the target for the development of new antimicrobials. Compounds (1835F03 and targocil) were recently shown to function as bacteriostatic inhibitors of wall teichoic acid (WTA) biosynthesis in S. aureus. To assess the value of targeting WTA biosynthesis in human infection, it was therefore of interest to verify the involvement of WTA in bacterial binding to human corneal epithelial cells (HCECs) and to assess the activities of inhibitors of WTA biosynthesis against clinical isolates of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) from cases of human keratitis. The 1835F03 MIC 90 s were 8 g/ml for MSSA keratitis isolates and >32 g/ml for MRSA keratitis isolates. The MIC 90 for the analog of 1835F03, targocil, was 2 g/ml for both MRSA and MSSA. Targocil exhibited little toxicity at concentrations near the MIC, with increased toxicity occurring at higher concentrations and with longer exposure times. Targocil activity was moderately sensitive to the presence of serum, but it inhibited extracellular and intracellular bacteria in the presence of HCECs better than vancomycin. Targocil-resistant strains exhibited a significantly reduced ability to adhere to HCECs.

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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In Vitro Antimicrobial Activity of Wall Teichoic Acid Biosynthesis Inhibitors against Staphylococcus aureus Isolates

Suzuki

Swoboda

Campbell

et al. 2011

Antimicrob Agents Chemother

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“…Adapted from (Sewell and Brown 2014) The first reported late-stage WTA biosynthesis inhibitor is targocil 21 (Scheme 12), which is a selective TarG inhibitor identified by the high-throughput screening (HTS) of a library of 55000 small molecules against wild-type S. aureus and a tarO-deletion mutant (Lee et al 2010;Swoboda et al 2010). Targocil has been proven to induce significant cell wall stress (Campbell et al 2012) and displayed a submicromolar MIC against MRSA.…”

Section: Lessons Learned From Druggable Targets In Bacteriamentioning

confidence: 99%

“…Targocil has been proven to induce significant cell wall stress (Campbell et al 2012) and displayed a submicromolar MIC against MRSA. Targocil treatment came with a high frequency of resistance selection at 8x MIC (Lee et al 2010)), which was substantially reduced in co-appli atio ith the β-lactam oxacillin, suggesting that the mechanism of resistance is an early-stage WTA biosynthesis gene mutation. In another screening of a focused library of 20000 small molecules bioactive against S. aureus performed by researchers from Merck, six additional TarG inhibitors were identified (Wang et al 2013).…”

Section: Lessons Learned From Druggable Targets In Bacteriamentioning

confidence: 99%

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

Klahn

Brönstrup

2016

Current Topics in Microbiology and Immunology

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Abstract:The development of bacterial resistance against current antibiotic drugs necessitates a continuous renewal of the arsenal of efficacious drugs. This imperative has not been met by the output of antibiotic research and development of the past decades for various reasons, including the declining efforts of large pharma companies in this area. Moreover, the majority of novel antibiotics are chemical derivatives of existing structures that represent mostly step innovations, implying that the available chemical space may be exhausted. This review negates this impression by showcasing recent achievements in lead finding and optimization of antibiotics that have novel or unexplored chemical structures. Not surprisingly, many of the novel structural templates like teixobactins, lysocin, griselimycin, or the albicidin/cystobactamid pair were discovered from natural sources. Additional compounds were obtained from the screening of synthetic libraries and chemical synthesis, including the gyrase-inhibiting NTBI s a d spiropyrimidinetrione, the tarocin and targocil inhibitors of wall teichoic acid synthesis, or the boronates and diazabicyclo[3.2

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Development of improved inhibitors of wall teichoic acid biosynthesis with potent activity against Staphylococcus aureus

Cited by 63 publications

References 12 publications

In Vitro Antimicrobial Activity of Wall Teichoic Acid Biosynthesis Inhibitors against Staphylococcus aureus Isolates

In Vitro Antimicrobial Activity of Wall Teichoic Acid Biosynthesis Inhibitors against Staphylococcus aureus Isolates

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

Medicinal Chemistry of β‐Lactam Antibiotics

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