A Structural Approach to Anti-Virulence: A Discovery Pipeline.

Michael McCarthy,Blake Morey,Madison Turner,Monica Goncalves,Allan Rod Merrill,Hannah Powell

doi:10.3390/microorganisms9122514

Abstract

The anti-virulence strategy is designed to prevent bacterial virulence factors produced by pathogenic bacteria from initiating and sustaining an infection. One family of bacterial virulence factors is the mono-ADP-ribosyltransferase toxins, which are produced by pathogens as tools to compromise the target host cell. These toxins are bacterial enzymes that exploit host cellular NAD+ as the donor substrate to modify an essential macromolecule acceptor target in the host cell. This biochemical reaction modifies the target macromolecule (often protein or DNA) and functions in a binary fashion to turn the target activity on or off by blocking or impairing a critical process or pathway in the host. A structural biology approach to the anti-virulence method to neutralize the cytotoxic effect of these factors requires the search and design of small molecules that bind tightly to the enzyme active site and prevent catalytic function essentially disarming the pathogen. This method requires a high-resolution structure to serve as the model for small molecule inhibitor development, which illuminates the path to drug development. This alternative strategy to antibiotic therapy represents a paradigm shift that may circumvent multi-drug resistance in the offending microbe through anti-virulence therapy. In this report, the rationale for the anti-virulence structural approach will be discussed along with recent efforts to apply this method to treat honey bee diseases using natural products.

Highlights

Since their serendipitous discovery by Alexander Fleming, antibiotics have been the basis in modern medicine for the treatment of bacterial diseases because of the lifesaving compounds produced by Florey during World War II
The anti-virulence or anti-infective approach shows great promise as an alternative to antibiotic therapy and may help alleviate the antibiotic resistance dilemma by targeting non-essential components of the bacterial pathogen, reducing the selective pressure on the organism to mutate or evolve. Natural products such as flavonoids have a bright future as potential agents for anti-virulence strategies for treating microbial pathogens
The second level of anti-virulence agent development requires the intervention of industry, such as the pharmaceutical or agricultural sectors

Summary

Introduction

Since their serendipitous discovery by Alexander Fleming, antibiotics have been the basis in modern medicine for the treatment of bacterial diseases because of the lifesaving compounds produced by Florey during World War II. The emergence of multidrug resistance bacteria has threatened to unravel this approach to human and animal health. The global spread of resistant microbes in all areas of disease treatment has left the antibiotic drug pipeline unable to meet demand since compounds are metabolized by voracious multi-drug resistant organisms [1–3]. The situation begs for new strategies to combat microbial pathogens [2,4–7]. A compelling, innovative, and alternative approach to antibiotic therapy is the antivirulence or anti-infective strategy that involves targeting virulence-associated rather than survival/fitness-relevant traits in the offending pathogen [8–13].

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