Proteobiotics are natural metabolites which are produced by fermentation process of specific probiotic strains. These small oligopeptidesTessema, Akalate. “Lactic Acid Bacteria and Culture Media for the Production of Potential Antivirulence Peptides against Salmonella Typhimurium.” M.Sc. Thesis.
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Antivirulence is the concept of blocking virulence factors. In regards to bacteria, the idea is to design agents that block virulence rather than kill bacteria en masse, as the current regime results in much more selective pressure (on antibiotic resistance). From the early 1950s onwards, a large number of antibiotics, due to the emergence of multidrug-resistant common pathogen strains (both gram-negative and gram-positive), became scarcely effective and not-useful. This scenario has stimulated the research for an alternative strategy focused on agents (antivirulence or antipathogenic agents) aimed to disarm microorganisms cause of infectious disease, without killing or inhibiting the growth of microorganisms themselves and therefore with limited selective pressure to promote the antibiotic resistance phenomenon.
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Early examples of the antivirulence approach include mainly the inactivation of bacterial toxins with anti-toxin antibodies administered to post-exposure patients (serological therapy that induces artificially acquired passive immunization). Since inactivation of toxin during infection has proven to be an effective way to prevent or alleviate the symptoms of acute disease, significant progress has been made in the development of novel anti-toxic monoclonal antibodies. Therefore, in October 2016 the US Food and Drug Administration (FDA) and in July 2018 the Italian Drug Agency (AIFA) approved the therapeutic use of a monoclonal antibody called bezlotoxumab (Zinplava) as a treatment aimed at reducing the recurrence of Clostridium difficile infection in patients at high risk of recurrence.Dickey, S.W, Cheung, G.Y.C, Otto, M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance.
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3,6-Disubstituted triazolo-thiadiazole compounds are under preclinical evaluation (including animal models) as antivirulence drugs against Staphylococcus aureus.Zhang J. et al., Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase, PNAS 16, 2014, 111(37)13517-13522 Other cell surface molecules in Gram-positive bacteria, involved in the adhesion process, without cell wall anchorage, are non proteinaceous adhesins like Wall Teichoic acids (WTAs) and lipoteichoic acids.
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The antivirulence strategy needs the knowledge of the pathogenic mechanisms and of the virulence factors that underlie them. Virulence factors are the weapons possessed by pathogens to cause damage to the host, hence they are molecules or bacterial cell structures involved in the various stages of pathogenesis such as adhesion, invasion and colonization and also in the ability to escape host defenses and to injury the host tissues by producing toxic molecules (bacterial endotoxins and exotoxins).
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Since WTAs are required for host infection and play important role in biofilm formation, it has been suggested that they are important virulence factors required for the establishment and spread of infection in a host. Therefore, the enzymes involved in WTAs biosynthesis can be considered as good targets for novel antivirulence agents that interfere with Gram-positive pathogenic process. One possible target is the WTA biosynthetic pathway because strains of S.aureus and Bacillus subtilis mutants in WTAs are not able to colonize the host tissue and show a greatly diminished ability to establish infection in animal models.Swoboda JG, Campbell J, Meredith TC, Walker S (2010) Wall teichoic acid function, biosynthesis, and inhibition.
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If we consider the important part played by MSCRAMMs in the first step of Gram-positive pathogenesis and of biofilm formation, new antivirulence agents could be developed by using as a target the enzyme responsible of linking such proteins to cell wall, that is the Sortase A (SrtA), rather than any single surface protein involved in the mechanism of virulence. Cascioferro, S., Raffa, D., Maggio, B., Raimondi, M. V., Schillaci, D., & Daidone, G. (2015). Sortase A inhibitors: Recent advances and future perspectives. Journal of Medicinal Chemistry, 58(23), 9108-9123. doi:10.1021/acs.jmedchem.5b00779 The SrtA is a membrane-bound cysteine transpeptidase that is responsible, in Gram-positive bacteria, for the covalent anchoring of surface proteins to bacterial cell wall.
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