Design and Synthesis of Aryl Ether Inhibitors of the Bacillus Anthracis Enoyl‐ACP Reductase

Abstract

The problem of increasing bacterial resistance to the current generation of antibiotics is well documented. This includes such pathogens as methicillin–resistant Staphylococcus aureus and the potential for developing drug–resistant pathogens for use as bioweapons, such as Bacillus anthracis. The biphenyl ether, antibacterial triclosan exhibits broad–spectrum activity and provides a potential scaffold for the development of new, broad–spectrum antibiotics targeting the fatty acid biosynthetic pathway, via inhibition of enoyl–acyl carrier protein reductase (ENR). We have utilized a structure–based approach to develop novel aryl ether analogs of triclosan that target ENR, the product of the FabI gene, from Bacillus anthracis (BaENR). Structure–based design methods were used for the expansion of the compound series including X-ray crystal structure determination, molecular docking, and QSAR methods. Structural modifications were made to both phenyl rings of the 2-phenoxyphenyl core. A number of compounds were derived that exhibited improved potency against BaENR and increased efficacy against both the Sterne strain of B. anthracis and the methicillin–resistant strain of S. aureus. X-ray crystal structures of BaENR in complex with triclosan and two other compounds help explain the improved efficacy of the new compounds and suggest future rounds of optimisation that might be used to improve their potency.

Staphylococcus aureus FabI: Inhibition, Substrate Recognition, and Potential Implications for In Vivo Essentiality

“…All residues interacting with the diphenyl ether inhibitors are located in three distinct regions (Figure 3), which exhibit substantial flexibility prior to cofactor and inhibitor binding. As described for numerous FabI orthologs and other SDR proteins, the substrate-binding loop (SBL, 194–204) is disordered or rearranged in our apo structures (Grimm et al, 2000; Tipparaju et al, 2008). In contrast to other FabI structures, however, the saFabI structures reveal flexibility of a second substrate-binding loop (SBL-2, 94–108) as well as the active site loop (ASL, 147–157).…”

Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

“…In our efforts to discover direct and effective inhibitors of the bacterial and parasitic enoyl-acyl reductases, we designed and synthesized a broad range of TRC analogs. These analogs were previously evaluated for biological activity against Bacillus anthracis [39] and Toxoplasma gondii . [40, 41] …”

Structural and Enzymatic Analyses Reveal the Binding Mode of a Novel Series of Francisella tularensis Enoyl Reductase (FabI) Inhibitors

“…19,20 Because of this, the diphenyl ether scaffold has received considerable attention in the antibacterial drug discovery arena. 21–27 Unfortunately, the diphenyl scaffold has significant disadvantages, including high serum binding and metabolic inactivation through glucuronidation and sulfation. The remaining scaffolds mentioned above also have significant hurdles which have limited their clinical utility to date.…”