A Quantitative Model to Estimate Drug Resistance in Pathogens.

Melanie Cushion,Aleksey Porollo,Frazier Baker

doi:10.3390/jof2040030

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 by Pneumocystis 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 on Pneumocystis jirovecii DHFR/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 aureus DHFR/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.

Highlights

Pneumocystis pneumonia (PCP) is a potentially lethal fungal infection affecting patients with an incompetent immune system, including patients with AIDS, autoimmune disorders, and after organ transplantation, as well as other morbidities requiring medically induced suppression of the immune system
We have recently developed a new tool for the amino acid co-variance analysis, CoeViz [27] that overcomes most of the limitations listed above for Direct Coupling Analysis (DCA)
Different models described in Methods were evaluated available for drug targets and theirfor variants jirovecii

Summary

Introduction

Pneumocystis pneumonia (PCP) is a potentially lethal fungal infection affecting patients with an incompetent immune system, including patients with AIDS, autoimmune disorders, and after organ transplantation, as well as other morbidities requiring medically induced suppression of the immune system. The cause of PCP in humans is Pneumocystis jirovecii, which like other fungi in the genus. Pneumocystis, do not respond to the commonly used anti-fungal therapies. A combination therapy, consisting of trimethoprim and sulfamethoxazole (TMP-SMX), which targets the folate biosynthesis pathway at 2 enzymatic steps, remains the primary option for the treatment and prophylaxis of PCP. J. Fungi 2016, 2, 30; doi:10.3390/jof2040030 www.mdpi.com/journal/jof.

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