Chemical Biology Study points to novel antibacterials

Axford LC, Agarwal PK, Anderson KH, Andrau LN, Atherall J, Barker S, Bennett JM, Blair M, Collins I, Czaplewski LG, Davies DT, Gannon CT, Kumar D, Lancett P, Logan A, Lunniss CJ, Mitchell DR, Offermann DA, Palmer JT, Palmer N, Pitt GR, Pommier S, Price D, Narasinga Rao B, Saxena R, Shukla T, Singh AK, Singh M, Srivastava A, Steele C, Stokes NR, Thomaides-Brears HB, Tyndall EM, Watson D, Haydon DJ.

Bioorg Med Chem Lett. 2013 Nov 4. pii: S0960-894X(13)01264-X. doi: 10.1016/j.bmcl.2013.10.058. [Epub ahead of print]

The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.

Chemical Biology study published describing the characterisation of novel antibacterial compounds

Stokes NR, Thomaides-Brears HB, Barker S, Bennett JM, Berry J, Collins I, Czaplewski LG, Gamble V, Lancett P, Logan A, Lunniss CJ, Peasley H, Pommier S, Price D, Smee C, Haydon DJ.

Antimicrob Agents Chemother. 2013 Dec;57(12):5977-86

The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 μg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 μg/ml for Streptococcus pneumoniae to 0.25 μg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10(-10) with compound A and <5.8 × 10(-11) with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.

Antibiotic Action, supported by the BSAC, the Medical Research Council, The Wellcome Trust and BBSRC, invited fifty international experts from academia, science, medicine and industry consider what lessons can be learnt from the last 40-years to aid the discovery and development of new antibacterial agents. In a ground breaking event speakers examined issues such as why interesting antibiotic molecules were not developed, to difficulties in developing antibiotic drugs for Gram negative infections.

A summary of the meeting can be found at:

http://antibiotic-action.com/2013/08/21/lessons-to-be-learnt-from-pharma-about-discovery-and-development-of-new-antibacterial-drugs-report-now-available/

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