The Microbial Toxin Microcin B17: Prospects for the Development of New Antibacterial Agents

Abstract

Microcin B17 (MccB17) is an antibacterial peptide produced by strains of Escherichia coli harboring the plasmid-borne mccB17 operon. MccB17 possesses many notable features. It is able to stabilize the transient DNA gyrase–DNA cleavage complex, a very efficient mode of action shared with the highly successful fluoroquinolone drugs. MccB17 stabilizes this complex by a distinct mechanism making it potentially valuable in the fight against bacterial antibiotic resistance. MccB17 was the first compound discovered from the thiazole/oxazole-modified microcins family and the linear azole-containing peptides; these ribosomal peptides are post-translationally modified to convert serine and cysteine residues into oxazole and thiazole rings. These chemical moieties are found in many other bioactive compounds like the vitamin thiamine, the anti-cancer drug bleomycin, the antibacterial sulfathiazole and the antiviral nitazoxanide. Therefore, the biosynthetic machinery that produces these azole rings is noteworthy as a general method to create bioactive compounds. Our knowledge of MccB17 now extends to many aspects of antibacterial–bacteria interactions: production, transport, interaction with its target, and resistance mechanisms; this knowledge has wide potential applicability. After a long time with limited progress on MccB17, recent publications have addressed critical aspects of MccB17 biosynthesis as well as an explosion in the discovery of new related compounds in the thiazole/oxazole-modified microcins/linear azole-containing peptides family. It is therefore timely to summarize the evidence gathered over more than 40 years about this still enigmatic molecule and place it in the wider context of antibacterials.

The manifold roles of microbial ribosomal peptide–based natural products in physiology and ecology

“…2), the prototypic molecule endowed with such modifications (72) and the first RiPP to have its biosynthesis reconstituted in vitro (73). The thiazole/oxazole rings of microcin B17 are made from Cys and Ser/Thr residues by a three-component B17 synthetase that catalyzes dehydration and cyclization to form azolines, which are subsequently oxidized to azoles (74). Peptides from the TOMM family include several toxins from pathogenic bacteria (streptolysin S from Streptococcus pyogenes and other Streptococcus species, listeriolysin S from Listeria monocytogenes (Table 1), clostridiolysin S from Clostridium botulinum and Clostridium sporogenes, and stapholysin S from Staphylococcus aureus RF122, whose structures all remain elusive) and other TOMMs from nonpathogenic bacterial species (71,74).…”

“…The thiazole/oxazole rings of microcin B17 are made from Cys and Ser/Thr residues by a three-component B17 synthetase that catalyzes dehydration and cyclization to form azolines, which are subsequently oxidized to azoles (74). Peptides from the TOMM family include several toxins from pathogenic bacteria (streptolysin S from Streptococcus pyogenes and other Streptococcus species, listeriolysin S from Listeria monocytogenes (Table 1), clostridiolysin S from Clostridium botulinum and Clostridium sporogenes, and stapholysin S from Staphylococcus aureus RF122, whose structures all remain elusive) and other TOMMs from nonpathogenic bacterial species (71,74). Those have been shown to exert different biological activities among which are antibacterial properties (microcin B17 from E. coli, klebsazolicin from Klebsiella pneumoniae, goadsporin from soil Streptomyces sp.…”

“…Pop5, respectively (77)). It has been firmly established that microcin B17 blocks DNA gyrase (74,78) and that phazolicin and klebsazolicin inhibit the ribosome (77), but the modes of action of other TOMM peptides remain largely unknown.…”

Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria

“…Overall, self-immunity of the producers relies either on specific immunity proteins encoded in the gene clusters that bind to the toxic entities making them inefficient, or on efflux systems, mainly ABC transporters, which ensure export of the microcins to the external medium and simultaneously self-immunity of the producing bacteria. As examples, self-immunity to MccJ25 is provided exclusively by McjD, a highly specific ABC exporter which ensures simultaneously export of the microcin (Beis and Rebuffat, 2019), while full self-immunity to MccB17 requires both an immunity protein McbG and an ABC exporter McbEF (Collin and Maxwell, 2019).…”

“…It causes covalent links between DNA gyrase and double stranded DNA, hence blocking DNA replication and maintenance. Similar to fluoroquinolones, MccB17 targets the cleavage of both DNA strands, which is a critical step in the DNA gyrase supercoiling cycle, but the MccB17-induced cleavage pattern is different from that of quinolones (for a review on MccB17 activity see Collin and Maxwell, 2019). The stringent role of the heterocycles in MccB17 activity has been evidenced (Roy et al, 1999).…”