The rapid and incessant rise in antibiotic-resistant bacteria represents a serious public health threat that must be addressed.1 Economic pressures have resulted in an overall decrease in the number of pharmaceutical companies with active antimicrobial research programs, underscoring the need for new sources of antibiotics.2 The broad, long-term goal of the proposed work is to meet this need by discovering novel macrolide antibiotics that directly address known resistance mechanisms by rational drug design. The mechanism of macrolide antibiotic drug action is known.3 These drugs bind the bacterial ribosome and prevent protein synthesis. Recently, crystal structures of various macrolide drugs (e.g., erythromycin, telithromycin, azithromycin) bound to ribosomal subunits have been solved, offering valuable structural insight as to how these compounds bind (i.e., contact with ribonucleotide residues) and how resistance mechanisms undermine drug action.4 Resistance mechanisms in which the ribosome itself is modified represent a formidable challenge to medicinal chemists.5 To address these particular mechanisms and facilitate chemical synthesis, the paradigm of natural product structure simplification (molecular editing)6 will be applied to the ketolide telithromycin, a 3rd generation semisynthetic drug derived from the flagship macrolide antibiotic erythromycin A and used in the clinic since 2004.
7 Aims i nclude (1) the application of computer-aided drug design (CADD) tools that will first evaluate a virtual library of selected macrolide analogues bound to both wild-type and resistant ribosomal subunits to determine the candidates most likely to have bioactivity and overcome resistance. In tandem, (2) chemical synthesis featuring novel methodology will provide access to material, which will (3) be screened against drug-susceptible and drug-resistant bacterial strains. This will serve to test the hypothesis that structural simplification of the complex macrolide architecture will directly address resistance without compromising bioactivity. Another round of CADD will serve to optimize the most promising candidates. Bioassays will measure success in this endeavor.
The increase in numbers of antibiotic-resistant bacterial strains represents a serious, global public health issue. The proposed project will address this need by preparing new drugs based on rational drug design with the assistance of computer modeling.
|Glassford, Ian; Teijaro, Christiana N; Daher, Samer S et al. (2016) Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry. J Am Chem Soc 138:3136-44|
|Faller, Christina E; Raman, E Prabhu; MacKerell Jr, Alexander D et al. (2015) Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design. Methods Mol Biol 1289:75-87|
|Raman, E Prabhu; MacKerell Jr, Alexander D (2013) Rapid estimation of hydration thermodynamics of macromolecular regions. J Chem Phys 139:055105|
|Wagh, Bharat; Paul, Tapas; Debrosse, Charles et al. (2013) Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin. ACS Med Chem Lett 4:1114-1118|
|Small, Meagan C; Lopes, Pedro; Andrade, Rodrigo B et al. (2013) Impact of ribosomal modification on the binding of the antibiotic telithromycin using a combined grand canonical monte carlo/molecular dynamics simulation approach. PLoS Comput Biol 9:e1003113|
|Velvadapu, Venkata; Glassford, Ian; Lee, Miseon et al. (2012) Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin. ACS Med Chem Lett 3:211-215|
|Wagh, Bharat; Paul, Tapas; Glassford, Ian et al. (2012) Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin. ACS Med Chem Lett 3:1013-1018|
|Velvadapu, Venkata; Paul, Tapas; Wagh, Bharat et al. (2011) Desmethyl Macrolide Analogues to Address Antibiotic Resistance: Total Synthesis and Biological Evaluation of 4,8,10-Tridesmethyl Telithromycin. ACS Med Chem Lett 2:68-72|
|Velvadapu, Venkata; Paul, Tapas; Wagh, Bharat et al. (2011) Total synthesis of (-)-4,8,10-tridesmethyl telithromycin. J Org Chem 76:7516-27|