Antibiotic alternatives: The potential of anti-virulence inhibitors

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Introduction
In 1928 Alexander Fleming discovered penicillin, an antibiotic that saved millions of lives during the Second World War. Fleming subsequently won the Nobel prize for Physiology and Medicine in 1945 and, in his prize lecture, anticipated the risk of antimicrobial resistance (AMR) [1]. His foresight proved right with the steady, and unchecked, rise of antimicrobial resistance.

A new wave of ‘superbugs’, both Gram-positive and -negative, have since become an increasingly recognized global issue. A renewed urgency to address the factors driving AMR has been driven by politicians and economists appreciating the potential consequences. In 2016, an AMR review [2] commissioned by the Wellcome Trust and UK Government stated that should AMR continue to worsen, by 2050 it could cost up to 10 million lives per year and upwards of 100 trillion US$ of economic output. Today, the annual mortality rate associated with AMR is already 700,000 individuals worldwide and could even be higher, if the deaths unrecorded in developing countries were to be included.

One of the leading causes for AMR is the incorrect and excessive prescription of antibiotics. Antibiotic abuse [3] continuously exerts selective pressure that generates strains resistant to antibiotics. Henceforth, it is imperative that the scientific community, along with the pharmaceutical industry, focuses on producing a new generation of antimicrobials to treat bacterial infections.

One such strategy is the development and application of anti-virulence (AV) drugs, which are designed to selectively target key virulence factors of pathogenic bacteria. The overall concept here is that AV drugs can render the bacteria less pathogenic and more vulnerable to clearance by the host immune system, and make them more susceptible to antibiotic killing [4,5].

Advantages of anti-virulence therapy

AV therapies selectively disarm the key virulence mechanisms of infecting pathogenic bacteria. Since most virulence factors are pathogen-specific, AV therapies act specifically and display a narrow-spectrum activity compared with conventional antibiotics.

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