Evolving Antibiotics against Resistance: a Potential Platform for Natural Product Development?

Kristofer Wollein Waldetoft,Sam P Brown,Paul A Hoskisson,James Gurney,Joseph Lachance,Gerard D Wright

doi:10.1128/mbio.02946-19

Kristofer Wollein Waldetoft, Sam P Brown + Show 4 more

Open Access

https://doi.org/10.1128/mbio.02946-19

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Journal: mBio	Publication Date: Dec 24, 2019
Citations: 4	License type: CC BY 4.0

Affiliation: Georgia Institute of Technology, University of Strathclyde

Abstract

To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance. However, the complex functions performed by antibiotics-combining, e.g., penetration of membranes, counteraction of resistance mechanisms, and interaction with molecular targets-have proven hard to achieve with current methods for drug development, including target-based screening and rational design. Here, we argue that we can meet the evolution of resistance in the clinic with evolution of antibiotics in the laboratory. On the basis of the results of experimental evolution studies of microbes in general and antibiotic production in Actinobacteria in particular, we propose methodology for evolving antibiotics to circumvent mechanisms of resistance. This exploits the ability of evolution to find solutions to complex problems without a need for design. We review evolutionary theory critical to this approach and argue that it is feasible and has important advantages over current methods for antibiotic discovery.

Highlights

To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance
Though not an established method for drug development, experimental evolution is a routine tool in evolutionary biology, and it has been successfully applied to antibiotic production by Actinobacteria [7], the source of the majority of antibiotic classes in clinical use
The potential for discovery of novel compounds is indicated by the fact that Actinobacteria—the antibiotic-producing bacteria that formed the basis of the “golden era” [2]— carry genes that encode many cryptic pathways [2, 8] that experimental evolution may turn on [7]

Summary

Introduction

To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance. We propose the following: when the utility of natural product antibiotics is threatened by resistance, we can experimentally evolve organisms that produce these compounds to circumvent the resistance mechanisms.

Results

Conclusion