Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities

Hafkin, Barry; Kaplan, Nachum; Murphy, Brian S.

doi:10.1128/aac.01741-15

Cited by 48 publications

(47 citation statements)

References 10 publications

(11 reference statements)

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“…With the anti-staphylococcal FabI inhibitor AFN-1252 in late phase clinical trials [14,78–80], this debate takes on a greater significance. AFN-1252 targets the enoyl-ACP reductase (FabI) of S. aureus .…”

Section: Evolutionary Changes In Bacterial Phospholipid Synthesis mentioning

confidence: 99%

Exogenous fatty acid metabolism in bacteria

2017

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Bacterial type II fatty acid synthesis (FASII) is a target for novel antibiotic development. All bacteria encode for mechanisms to incorporate exogenous fatty acids, and some bacteria can use exogenous fatty acids to bypass FASII inhibition. Bacteria encode three different mechanisms for activating exogenous fatty acids for incorporation into phospholipid synthesis. Exogenous fatty acids are converted into acyl-CoA in Gammaproteobacteria such as E. coli. Acyl-CoA molecules constitute a separate pool from endogenously synthesized acyl-ACP. Acyl-CoA can be used for phospholipid synthesis or broken down by β-oxidation, but cannot be used for lipopolysaccharide synthesis. Exogenous fatty acids are converted into acyl-ACP in some Gram-negative bacteria. The resulting acyl-ACP undergoes the same fates as endogenously synthesized acyl-ACP. Exogenous fatty acids are converted into acyl-phosphates in Gram-positive bacteria, and can be used for phospholipid synthesis or become acyl-ACP. Only the order Lactobacillales can use exogenous fatty acids to bypass FASII inhibition. FASII shuts down completely in presence of exogenous fatty acids in Lactobacillales, allowing Lactobacillales to synthesize phospholipids entirely from exogenous fatty acids. Inhibition of FASII cannot be bypassed in other bacteria because FASII is only partially down-regulated in presence of exogenous fatty acid or FASII is required to synthesize essential metabolites such as β-hydroxyacyl-ACP. Certain selective pressures such as FASII inhibition or growth in biofilms can select for naturally occurring one step mutations that attenuate endogenous fatty acid synthesis. Although attempts have been made to estimate the natural prevalence of these mutants, culture-independent metagenomic methods would provide a better estimate.

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Section: Evolutionary Changes In Bacterial Phospholipid Synthesis mentioning

confidence: 99%

Exogenous fatty acid metabolism in bacteria

2017

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“…The finding that HSA prevented the use of exogenous oleic acid by S. aureus to promote the rate of daptomycin inactivation indicated that this process is likely to be entirely dependent upon the FASII pathway in vivo . AFN-1252 is a FASII pathway inhibitor which blocks FabI and has shown potent activity against S. aureus in both pre-clinical and clinical testing [18,19]. Based on our previous findings [9], and the data described above, we hypothesised that AFN-1252 would enhance daptomycin activity against S. aureus by blocking the production of phospholipid decoys.…”

Section: Resultsmentioning

confidence: 98%

“…We have shown previously that inhibition of the FabF component of the FASII fatty acid synthetic pathway, using the antibiotic platensimycin, completely blocked phospholipid release [9,10]. Whilst platensimycin is unsuitable as a therapeutic drug due to poor pharmacological properties, the FabI inhibitor AFN-1252 shows more promising characteristics and a pro-drug variant is currently undergoing phase 2 clinical trials [18,19]. However, despite excellent in vitro activity, the therapeutic value of inhibitors of fatty acid synthesis as mono-therapeutic agents has attracted much debate [20,21].…”

Section: Introductionmentioning

confidence: 99%

A FASII inhibitor prevents staphylococcal evasion of daptomycin by inhibiting phospholipid decoy production

Pee

Pader

Ledger

et al. 2018

Preprint

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30Daptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive 31 pathogens such as methicillin-resistant Staphylococcus aureus. We have shown recently that S. aureus 32 can evade daptomycin by releasing phospholipid decoys that sequester and inactivate the antibiotic, 33 leading to treatment failure. Since phospholipid release occurs via an active process we hypothesised 34 that it could be inhibited, thereby increasing daptomycin efficacy. To identify opportunities for 35 therapeutic interventions that block phospholipid release, we first determined how the host 36 environment influenced the release of phospholipids and inactivation of daptomycin by S. aureus. The 37 addition of certain host-associated fatty acids to the growth medium enhanced phospholipid release. 38

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“…The drug has recently completed U.S. phase 2 clinical trials for ABSSSI with favorable outcomes. 225 A prodrug formulation, Debio 1450, allowing for oral and IV formulations is also currently in phase 2 clinical trials for ABSSSI. 226 Structurally, Debio 1452 consists of a 3-methyl-benzofuran and an oxo-tetrahydro-naphthyridine linked by an N -methylpropenamide ( Figure 14A ).…”

Section: Discussionmentioning

confidence: 99%

Recent advances in the rational design and optimization of antibacterial agents

et al. 2016

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This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents. The discussion of the agents focuses on the rational design strategies employed and the synthetic medicinal chemistry and structure-based design techniques utilized by the scientists involved in the discoveries, including such methods as ligand- and structure-based strategies, structure-activity relationship (SAR) expansion strategies, and novel synthetic organic chemistry methods. As such, the discussion is limited to small-molecule therapeutics that have confirmed macromolecular targets and encompasses only a fraction of all antibacterial agents recently approved or in late-stage clinical trials. The antibacterial agents selected have been recently approved for use on the U.S. or European markets or have shown promising results in phase 2 or phase 3 U.S. clinical trials.

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Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities

Cited by 48 publications

References 10 publications

Exogenous fatty acid metabolism in bacteria

Exogenous fatty acid metabolism in bacteria

A FASII inhibitor prevents staphylococcal evasion of daptomycin by inhibiting phospholipid decoy production

Recent advances in the rational design and optimization of antibacterial agents

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