Microcin H47: A Class IIb Microcin with Potent Activity Against Multidrug Resistant Enterobacteriaceae

Abstract

Microcin H47 (MccH47) is an antimicrobial peptide produced by some strains of Escherichia coli that has demonstrated inhibitory activity against enteric pathogens in vivo and has been heterologously overexpressed in proof-of-concept engineered probiotic applications. While most studies clearly demonstrate inhibitory activity against E. coli isolates, there are conflicting results on the qualitative capacity for MccH47 to inhibit strains of Salmonella. Here, we rectify these inconsistencies via the overexpression and purification of a form of MccH47, termed MccH47-monoglycosylated enterobactin (MccH47−MGE). We then use purified MccH47 to estimate minimum inhibitory concentrations (MICs) against a number of medically relevant Enterobacteriaceae, including Salmonella and numerous multidrug resistant (MDR) strains. While previous reports suggested that the spectrum of activity for MccH47 is quite narrow and restricted to activity against E. coli, our data demonstrate that MccH47 has broad and potent activity within the Enterobacteriaceae family, suggesting it as a candidate for further development toward treating MDR enteric infections.

Antibacterial Activity of Bacteriocinogenic Commensal Escherichia coli against Zoonotic Strains Resistant and Sensitive to Antibiotics

“…MccV, despite a low rate of growth inhibition, was mostly effective against multidrug-resistant strains, also in co-occurrence with ColK. Different indications regarding the activity of microcins against antibiotic-resistant strains were presented by Palmer et al [52], who showed that purified MccH47 has broad and potent activity against medically relevant multidrug-resistant members of Enterobacteriaceae.…”

“…Studies on the activity of bacteriocins, as an alternative to adjunctive therapy with antibiotics, and trials focused on probiotic bacteria are intensively conducted [31][32][33][34]. They concern mostly the bacteriocins of Gram-positive bacteria [35][36][37][38][39], but colicins and microcins are also tested as proteins with activity against pathogenic Gram-negative bacteria [40][41][42][43][44][45][46][47][48][49][50], including a few studies related to antibiotic-resistant strains [51,52]. However, nonclinical strains of animal origin, derived from farm animals that are particularly resistant to antibiotics, may reveal a distinct profile of sensitivity to bacteriocins.…”

Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria

“…MccH47 is bactericidal and targets the membrane bound F 0 proton channel subunits of ATP synthase (Trujillo et al, 2001;Rodriguez and Laviña, 2003;Palmer et al, 2020), causing an unregulated influx of protons. It uses FepA-, Cir-, Fiu-TonB dependent receptors to reach its inner membrane target (Patzer et al, 2003).…”

“…Likewise, MccH47 has demonstrated a potent effect against Enterobacteriaceae MDR strains including Salmonella and E. coli carbapenemase, extended spectrum β-lactamase and metallo-β-lactamase producers. MccH47 has MIC values less than 75 μg/mL (13 μM) for all tested strains ( Palmer et al, 2020 ).…”

“…When inside bacteria, microcins interfere and perturb a variety of bacterial mechanisms, such as transcription (Adelman et al, 2004), translation (Metlitskaya et al, 2006), DNA structure (Vizán et al, 1991), mannose transport (Bieler et al, 2006), energy production (Trujillo et al, 2001;Zhao et al, 2015), or the cell envelope function (Destoumieux-Garzón et al, 2003;Gerard et al, 2005;Zhao et al, 2015). Due to their specific characteristics and complex mechanisms of action, microcins are viewed as a possible alternative to conventional antibiotics, helping with the immediate AMR problem (Cotter et al, 2013;Mills et al, 2017;Lu et al, 2019;Palmer et al, 2020). Because of their narrow spectrum of inhibition, they would potentially have less side effects than antibiotics, allowing preservation of the microbiota diversity and minimizing the risk of resistance dissemination.…”