Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model

Banevicius, Mary Anné; Kaplan, Nachum; Hafkin, Barry; Nicolau, David P.

doi:10.1179/1973947812y.0000000061

Cited by 40 publications

(47 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although previous work suggested that fatty acids and phospholipids of chlamydial membranes are obtained from the host (45), our study shows that FASII is nonetheless essential for chlamydial replication. AFN-1252 is effective in cell culture against C. trachomatis and has pharmacological properties that make it an effective agent against S. aureus infections (36,46). However, its potency may have to be improved in order for it to be effectively deployed to treat C. trachomatis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

Yao

AbdelRahman

Robertson

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Chlamydia trachomatis has a phospholipid composition that resembles its eukaryotic host, but it contains branched-chain fatty acids of chlamydial origin. Results: The inhibition of the enoyl-acyl carrier protein reductase (FabI) in chlamydial fatty acid synthesis blocks C. trachomatis replication. Conclusion: Bacterial FASII is required for C. trachomatis proliferation. Significance: FabI is a therapeutic target against C. trachomatis.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Thus, AFN-1252 is a sharp tool to study the effects of FASII inhibition on C. trachomatis replication in light of its selectivity, its binding affinity, and the absence of off-target effects on human cells (11,36).…”

Section: ⅐Afn-1252 Complex These Data Indicated That Afn-1252 Inhibitedmentioning

confidence: 99%

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

Yao

AbdelRahman

Robertson

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…236 Affinium licensed the program in 2002 and conducted further structure optimization leading to AFN-1252 (39). 232,[238][239][240][241][242][243][244][245] In February 2014, Debiopharm Group (Lausanne, Switzerland) acquired Affinium's antibiotic assets, including both 39 and a prodrug of AFN-1252, Debio-1450 (AFN-1720). 246 The prodrug, Debio-1450, was assessed in two phase-I studies (NCT02162199 and NCT02214433), with a third (NCT02595203) scheduled for completion in December 2015.…”

Section: Compounds Undergoing Clinical Evaluationmentioning

confidence: 99%

Antibiotics in the clinical pipeline at the end of 2015

2016

View full text Add to dashboard Cite

There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

show abstract

“…Thus, acc knockouts must scavenge lipoate as well as fatty acids from the host, and our experiments illustrate that the quality and/or availability of these nutrients in mice attenuates the virulence of the bacteria. Our data provide a mechanistic rationale for the observed efficacy of the ACC inhibitors against S. aureus infections (21) and for the lack of acc mutations arising in animals treated with AFN-1252 (6,22) or other FASII inhibitors (23)(24)(25)(26).…”

mentioning

confidence: 99%

Staphylococcus aureus Fatty Acid Auxotrophs Do Not Proliferate in Mice

Parsons

Frank

Rosch

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Inactivation of acetyl-coenzyme A (acetyl-CoA) carboxylase confers resistance to fatty acid synthesis inhibitors in Staphylococcus aureus on media supplemented with fatty acids. The addition of anteiso-fatty acids (1 mM) plus lipoic acid supports normal growth of ⌬accD strains, but supplementation with mammalian fatty acids was less efficient. Mice infected with strain RN6930 developed bacteremia, but bacteria were not detected in mice infected with its ⌬accD derivative. S. aureus bacteria lacking acetyl-CoA carboxylase can be propagated in vitro but were unable to proliferate in mice, suggesting that the acquisition of inactivating mutations in this enzyme is not a mechanism for the evasion of fatty acid synthesis inhibitors.T he steady increase in multidrug-resistant Staphylococcus aureus prevalence has spurred the search for novel antibiotics to attack this clinically important organism (1). The bacterial type II fatty acid biosynthesis system (FASII) is a novel target that has engendered considerable attention, and there are multiple natural-product antibiotics that target the pathway (2). Most Gramnegative bacteria are susceptible to FASII inhibitors even when exogenous fatty acids are provided because they lack the ability to activate exogenous fatty acids to produce acyl carrier proteins (ACPs) and synthesize the hydroxyacyl-ACPs to support lipopolysaccharide biosynthesis (2). However, the behavior of Grampositive bacteria is different. These organisms do not produce hydroxy-fatty acids, and they are capable of incorporating exogenous fatty acids by ligating them to ACPs (3). These acyl-ACPs are either elongated by the FASII system or incorporated into phospholipids via the acyl-PO 4 /acyl-ACP-specific PlsX/PlsY/PlsC acyltransferase system (3). Thus, the FASII pathway can be inactivated through genetic deletions or FASII drugs in S. agalactiae, and the organism is able to grow if supplied with an exogenous fatty acid supplement (4). In S. pneumoniae, endogenous fatty acid synthesis is repressed in the presence of exogenous fatty acids, leading to the replacement of endogenous fatty acids with those provided in the medium even if FASII is not chemically or genetically inactivated (3, 4). Although S. aureus also incorporates exogenous fatty acids into membrane phospholipids via acyl-ACP, FASII inhibitors remain effective against this Gram-positive organism even in the presence of exogenous fatty acids (3).AFN-1252 is a compound in clinical development that blocks the enoyl-ACP reductase step of S. aureus FASII (5-7). Two classes of AFN-1252-resistant S. aureus mutants were isolated (3). One class consists of missense mutations in the fabI gene that lead to the production of a mutant FabI protein that is refractory to AFN-1252. When exogenous fatty acids were supplied in the media during selection, AFN-1252-resistant clones appeared 100 times more frequently (3). Genetic analysis showed that these isolates harbored mutations that completely inactivated one of the four genes required for acetyl-coenzyme A (ac...

show abstract

Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model

Cited by 40 publications

References 9 publications

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

Antibiotics in the clinical pipeline at the end of 2015

Staphylococcus aureus Fatty Acid Auxotrophs Do Not Proliferate in Mice

Contact Info

Product

Resources

About