Peptide Deformylase Inhibitors as Antibacterial Agents: Identification of VRC3375, a Proline-3-Alkylsuccinyl Hydroxamate Derivative, by Using an Integrated Combinatorial and Medicinal Chemistry Approach

Chen, D.; Hackbarth, C J; Ni, Zi-Jie; Wu, Charlotte; Wang, W.; Jain, Rakesh; He, Yan; Bracken, Kathryn; Weidmann, Beat; Patel, Dinesh V.; Trias, Joaquim; White, Richard; Yuan, Zhengqiu

doi:10.1128/aac.48.1.250-261.2004

Cited by 60 publications

(55 citation statements)

References 31 publications

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“…When such inhibitors were discovered (13,66,68,145,261,401), including the previously mentioned natural product antibacterial, actinonin (Fig. 4A) (68), resistance to inhibitors arose as expected, at a high frequency (10 Ϫ7 in permeable E. coli [13]), due to mutations in the fmt gene.…”

Section: Single-enzyme Targets Of Novel Inhibitors In Clinical Trialsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,142

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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Section: Single-enzyme Targets Of Novel Inhibitors In Clinical Trialsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,142

961

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“…6, compound 3), the first PDF inhibitor that has advanced through phase 2 clinical trials (http://www.clinicaltrials.gov). Although early PDF inhibitors were recognized particularly for their microbiological activity against staphylococci, especially MRSA (203), GSK1322322 also may have useful activity against S. pneumoniae and H. influenzae, with MICs of Յ4 g/ml against these organisms in addition to drug-resistant staphylococci (204,205). Clinical studies in healthy subjects showed good penetration of the inhibitor into epithelial lining fluid and alveolar macrophages (206).…”

Section: Pdf Inhibitorsmentioning

confidence: 99%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting.

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“…Based on structural (7,39,41) and mechanistic design, as well as high-throughput screening, several classes of PDF inhibitors (PDF-I) have been studied previously (64). Thus far, only compounds having hydroxamic acid-chelating or N-formyl hydroxylamine-chelating groups show potent enzyme inhibition, good antibacterial activity, and in vivo efficacy, including oral activity (9,12,27).…”

mentioning

confidence: 99%