Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents

Payne, D. J.; Miller, William H.; Berry, Valerie; Brosky, John; Burgess, Walter J.; Chen, Emile; DeWolf, Walter E.; Fosberry, Andrew; Greenwood, Rebecca; Head, Martha S.; Heerding, Dirk A.; Janson, Cheryl A.; Jaworski, Deborah D.; Keller, Paul M.; Manley, Peter J.; Moore, Terrance; Newlander, Kenneth A.; Pearson, S.; Polizzi, Brian J.; Qiu, Xiayang; Rittenhouse, Stephen; Slater-Radosti, Courtney; Salyers, Kevin L.; Seefeld, Mark A.; Smyth, Martin G.; Takata, Dennis T.; Uzinskas, Irene N.; Vaidya, Kalindi; Wallis, Nicola G.; Winram, Scott B.; Yuan, Catherine C.K.; Huffman, William F.

doi:10.1128/aac.46.10.3118-3124.2002

Cited by 155 publications

(141 citation statements)

References 14 publications

(11 reference statements)

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“…Some were shown to inhibit synthesis of soluble peptidoglycan in whole cells, but no other MMS inhibition was measured (119,395). The lack of this negative control lowers the value of (396) Imidazoles (154) Thiopyridines (214) Aminopyridines (177,258,294) and -K) the finding. Examples of these compounds and the enzymes they preferentially inhibit are shown in Fig.…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 96%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,138

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: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 96%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,138

961

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“…One of the reasons for this failure was the inability of these lead compounds to cross the bacterial cell wall. A second reason was that the narrow spectrum of the antibactericidal activities of these lead compounds did not meet the requirement for further development (Fan et al , 2002; Jarvest et al , 2002; Payne et al , 2002). The number of antibiotics approved by the FDA has steadily decreased in the last two decades, while the total number of new molecular entities has remained about the same (Figure 1A).…”

Section: Discovery and Development Of New Antibiotics – Issues And Nementioning

confidence: 99%

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Zheng

Sun

Simeonov

2017

British J Pharmacology

213

200

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Infectious diseases account for nearly one fifth of the worldwide death toll every year. The continuous increase of drug‐resistant pathogens is a big challenge for treatment of infectious diseases. In addition, outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug‐resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared with previous decades. In parallel with this, is an increase in the number of drug‐resistant bacteria. For these threats and challenges to be countered, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combinations using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutic agents such as narrow spectrum antibiotics against drug‐resistant bacteria for these global challenges.Linked ArticlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc

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“…Several synthetic FabI inhibitors, including 1,4-disubstituted imidazoles, 16) aminopyridines, 17) naphthyridinones, 18,19) and thiopyridines 20) have been reported in previous studies. Cephalochromin, 11) vinaxanthone, 21) EGCG, 22) and flavonoids 23) have all been identified as natural FabI inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Aquastatin A, a New Inhibitor of Enoyl-Acyl Carrier Protein Reductase from Sporothrix sp. FN611

Kwon

Fang

et al. 2009

Biological & Pharmaceutical Bulletin

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Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In this study, we determined that a fungal metabolite from Sporothrix sp. FN611 potently inhibited the enoyl-ACP reductase (FabI) of Staphylococcus aureus. Its structure identified the metabolite as aquastatin A by the MS and NMR data. Aquastatin A inhibited S. aureus FabI with an IC 50 of 3.2 m mM. It also prevented the growth of S. aureus and methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration of 16-32m mg/ml. Aquastatin A also exerted an inhibitory effect against the FabK isoform, an enoyl-ACP reductase of Streptococcus pneumoniae, with an IC 50 of 9.2 m mM. The degalactosylation of aquastatin A did not affect the FabI and FabK-inhibitory or antibacterial activities, thereby suggesting that the sugar moiety within its molecular structure was not involved in these activities. The inhibitory effects of aquastatin A and its degalactosylated derivative on enoyl-ACP reductases and bacterial viability are reported for the first time in this study; these effects point to the potential that aquastatin A may be developed into a new broad-spectrum antibacterial and anti-MRSA agent.

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Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents

Cited by 155 publications

References 14 publications

Challenges of Antibacterial Discovery

Challenges of Antibacterial Discovery

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Aquastatin A, a New Inhibitor of Enoyl-Acyl Carrier Protein Reductase from Sporothrix sp. FN611

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