Fatty acids as anti-virulence agents against pathogenic bacteria

An increased interest for alternative treatment options against bacterial infections is arising in both research and society due to antibiotic resistance development and lack of sufficient treatment against some bacterial infections. Free fatty acids (FFAs) have been known for decades to have antimicrobial properties against multiple bacterial pathogens. Recently, it was discovered that FFAs could have anti-virulent properties against some pathogens, which increased the interest for studying FFAs as potential anti-virulent agents against bacterial infections.


Here we examine how FFAs can cause an antimicrobial and anti-virulent response in pathogens, more specifically the foodborne pathogen Listeria monocytogenes, which presents a high fatality rate despite antibiotic treatment. Previously, it was observed that FFAs with antimicrobial properties against L. monocytogenes could inhibit the activity of the major virulence regulator PrfA. The inhibition of PrfA activity reduces virulence gene expression and
results in an anti-virulent effect. Since only FFAs with both or neither of the effects have been detected so far, we speculated if the antimicrobial and anti-virulent activities of the FFAs could
be linked. We specifically investigated a link between the two activities and the underlying mechanisms of the antimicrobial and anti-virulent effect. Our data clearly indicate that there is
no obvious link or connection between the antimicrobial and anti-virulent effect of FFAs on L. monocytogenes. Additionally, FFAs with only anti-virulent properties were detected, supporting that the two activities are not linked. For the antimicrobial response to FFAs, our data reveal that both the transcriptional regulator Catabolite control protein A (CcpA) and Nacetylglucosamine (GlcNAc) glycosylation of wall teichoic acids confer sensitivity towards antimicrobial FFAs. Upon constant exposure to two different antimicrobial FFAs, mutations occurred in ccpA or the gene coding for GlcNAc glycosylation, which led to FFA tolerance. The tolerance occurred based on a more hydrophilic surface, which repulsed the FFAs from the bacterial surface. For the anti-virulent activity of the FFAs, we showed that anti-virulent FFAs
could bind directly to PrfA in vitro and inhibit PrfA activity. This inhibition reduces the virulence gene expression in vivo. Altogether, since the antimicrobial and anti-virulent effects of the FFAs are not linked, we show that despite resistance development towards the antimicrobial effect of the FFAs strains stay sensitive towards the anti-virulent activity of the FFAs. This indicates
that FFAs could be potent treatment compounds despite resistance development.