Evolutionary druggability for low-dimensional fitness landscapes toward new metrics for antimicrobial applications

Author:

Guerrero Rafael F1ORCID,Dorji Tandin2,Harris Ra'Mal M3ORCID,Shoulders Matthew D3ORCID,Ogbunugafor C Brandon3456ORCID

Affiliation:

1. Department of Biological Sciences, North Carolina State University

2. Department of Mathematics and Statistics, University of Vermont

3. Department of Chemistry, Massachusetts Institute of Technology

4. Department of Ecology and Evolutionary Biology, Yale University

5. Santa Fe Institute

6. Public Health Modeling Unit, Yale School of Public Health

Abstract

The term ‘druggability’ describes the molecular properties of drugs or targets in pharmacological interventions and is commonly used in work involving drug development for clinical applications. There are no current analogues for this notion that quantify the drug-target interaction with respect to a given target variant’s sensitivity across a breadth of drugs in a panel, or a given drug’s range of effectiveness across alleles of a target protein. Using data from low-dimensional empirical fitness landscapes composed of 16 β-lactamase alleles and 7 β-lactam drugs, we introduce two metrics that capture (i) the average susceptibility of an allelic variant of a drug target to any available drug in a given panel (‘variant vulnerability’), and (ii) the average applicability of a drug (or mixture) across allelic variants of a drug target (‘drug applicability’). Finally, we (iii) disentangle the quality and magnitude of interactions between loci in the drug target and the seven drug environments in terms of their mutation by mutation by environment (G x G x E) interactions, offering mechanistic insight into the variant variability and drug applicability metrics. Summarizing, we propose that our framework can be applied to other datasets and pathogen-drug systems to understand which pathogen variants in a clinical setting are the most concerning (low variant vulnerability), and which drugs in a panel are most likely to be effective in an infection defined by standing genetic variation in the pathogen drug target (high drug applicability).

Funder

National Institutes of Health

National Science Foundation

Publisher

eLife Sciences Publications, Ltd

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