AFN-1252, a FabI Inhibitor, Demonstrates a Staphylococcus-Specific Spectrum of Activity

Karlowsky, James A.; Kaplan, Nachum; Hafkin, Barry; Hoban, Daryl J.; Zhanel, George G.

doi:10.1128/aac.00400-09

Cited by 70 publications

(80 citation statements)

References 6 publications

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“…This specific antistaphylococcal inhibitor of FabI had MIC values of Յ0.12 g/ml against all clinical isolates of S. aureus (n ϭ 502) and Staphylococcus epidermidis (n ϭ 51) tested, including methicillin-resistant strains. Poor activity was reported against streptococci, enterococci, and Gram-negative isolates, with MIC 90 values of Ͼ4 g/ml (216). Biochemical, structural, and microbiological studies confirmed that fatty acid biosynthesis was the killing target for the compound (217).…”

Section: Fatty Acid Synthesis Inhibitorsmentioning

confidence: 98%

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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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Section: Fatty Acid Synthesis Inhibitorsmentioning

confidence: 98%

“…Scientists from Affinium Pharmaceuticals have described an iterative structure-guided chemistry program targeting FabI from S. aureus (214,215) from which they subsequently identified AFN-1252, a 3-methylbenzofuran linked to an oxotetrahydronaphthyridine by an N-methylpropenamide (216) (Fig. 6, compound 4).…”

Section: Fatty Acid Synthesis Inhibitorsmentioning

confidence: 99%

Investigational Antimicrobial Agents of 2013

Pucci

Bush

2013

Clin Microbiol Rev

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“…The Affinium clinical candidate AFN-1252 (Fig. 4F), which is closely related to its GSK progenitors, is staphylococcus specific in spectrum and has no demonstrable S. pneumoniae or S. pyogenes activity (184). No data on resistance selection by the GSK or Affinium FabI inhibitors are available.…”

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

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,136

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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“…AFN-1252 is a potent and selective inhibitor of FabI that has no known off-target effects (20,24,36,37). AFN-1252 inhibits the growth of bacteria with a single essential FabI, including intracellular pathogens (18,20,24,38), but is ineffective against bacterial genes encoding the other enoyl-acyl carrier protein reductase isoforms (39). These data, coupled with the observation that S. aureus accD mutants are refractory to AFN-1252 (14), show there is little or no off-target toxicity of this drug.…”

Section: Resultsmentioning

confidence: 99%

Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes

et al. 2016

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Listeria monocytogenes is a facultative intracellular Gram-positive bacterium that is the primary cause of the disease listeriosis (1). The environmentally hardy and ubiquitous L. monocytogenes is ingested through contaminated food products and can cause noninvasive diseases, such as gastroenteritis, or invade through the intestinal epithelium to cause central nervous system infections or bacteremia. L. monocytogenes poses a major medical threat for pregnant women and immunocompromised patients. Yearly outbreaks of L. monocytogenes in a variety of food products from fruits to ice cream underscore the need to understand the requirements for L. monocytogenes infection and discover new methods to inhibit the growth of L. monocytogenes.The phospholipids of L. monocytogenes are composed of branched-chain fatty acids synthesized by the L. monocytogenes type II fatty acid synthesis system. Decreasing the synthesis of branchedchain fatty acids by the genetic deletion of the branched-chain ␣-keto acid dehydrogenase compromises the environmental survival and intracellular pathogenesis of L. monocytogenes (2-6). The pathways for fatty acid synthesis, phospholipid synthesis, and exogenous fatty acid incorporation of L. monocytogenes are predicted to be the same as those for the phylogenetically related and wellcharacterized Staphylococcus aureus system (Fig. 1). Fatty acids are synthesized using a prototypical type II bacterial fatty acid synthesis, with 2-methylbutyryl-coenzyme A (CoA) as the primer, to make branch-chain fatty acids (3,5,(7)(8)(9)). An acyl-acyl carrier protein (ACP) of the appropriate length is used as the acyl donor by the PlsX/Y/C system to make phosphatidic acid from glycerol-3-phosphate (10, 11). Exogenous fatty acids are incorporated via the fatty acid kinase system (12)(13)(14). An unusual feature of L. monocytogenes fatty acid synthesis is the presence of four genes that may encode enoyl-acyl carrier protein reductases, including a FabI, a FabL, and two FabK isoforms, rather than the single FabI found in S. aureus and a variety of other bacterial pathogens. The FabL isoform was discovered in the phylogenetically related Bacillus, which also has a FabI (15). Both proteins function in fatty acid synthesis in Bacillus. The FabK isoform is a flavoprotein unrelated to FabI that was originally discovered in Streptococcus pneumoniae (16). The Enterococcus faecalis genome encodes both FabI and FabK, but FabI is responsible for the bulk of fatty acid synthesis while FabK plays a minor role in supporting fatty acid synthesis (17).The goal of this study was to identify which of the putative L. monocytogenes reductase genes code for functional enoyl-acyl carrier protein reductases, assess their contribution to supporting type II bacterial fatty acid synthesis, and determine their role in planktonic and intracellular growth. Complete inhibition of FabI using the FabI selective inhibitor AFN-1252 reduced the fatty acid synthesis of L. monocytogenes strain 10403S by 80% and reduced the growth rate of L. monocytog...

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AFN-1252, a FabI Inhibitor, Demonstrates a Staphylococcus-Specific Spectrum of Activity

Cited by 70 publications

References 6 publications

Investigational Antimicrobial Agents of 2013

Investigational Antimicrobial Agents of 2013

Challenges of Antibacterial Discovery

Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes

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