title: A Quantitative Model to Estimate Drug Resistance in Pathogens.
abstract: Pneumocystis pneumonia (PCP) is an opportunistic infection that occurs in humans and other mammals with debilitated immune systems. These infections are caused by fungi in the genus Pneumocystis, which are not susceptible to standard antifungal agents. Despite decades of research and drug development, the primary treatment and prophylaxis for PCP remains a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) that targets two enzymes in folic acid biosynthesis, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), respectively. There is growing evidence of emerging resistance byPneumocystis jirovecii(the species that infects humans) to TMP-SMX associated with mutations in the targeted enzymes. In the present study, we report the development of an accurate quantitative model to predict changes in the binding affinity of inhibitors (Ki,IC50) to the mutated proteins. The model is based on evolutionary information and amino acid covariance analysis. Predicted changes in binding affinity upon mutations highly correlate with the experimentally measured data. While trained onPneumocystis jiroveciiDHFR/TMP data, the model shows similar or better performance when evaluated on the resistance data for a different inhibitor of PjDFHR, another drug/target pair (PjDHPS/SMX) and another organism (Staphylococcus aureusDHFR/TMP). Therefore, we anticipate that the developed prediction model will be useful in the evaluation of possible resistance of the newly sequenced variants of the pathogen and can be extended to other drug targets and organisms.
authors.affiliation: Department of Electrical Engineering and Computing Systems, University of Cincinnati, Cincinnati, OH, USA 45221; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 45229.
authors.forename: Frazier N
authors.initials: FN
authors.lastname: Baker
authors.affiliation: Department of Internal Medicine University of Cincinnati College of Medicine, Cincinnati, OH, USA 45267; melanie; The Veterans Affairs Medical Center, Cincinnati, OH, USA 45220.
authors.forename: Melanie T
authors.initials: MT
authors.lastname: Cushion
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 45229; Department of Biomedical Informatics, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 45267.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Porollo
keywords: Pneumocystis jirovecii; Pneumocystis pneumonia; QSAR; amino acid coevolution; amino acid covariance; drug resistance; folate biosynthesis