Microcins reveal natural mechanisms of bacterial manipulation to inform therapeutic development

Abstract

Microcins are an understudied and poorly characterized class of antimicrobial peptides. Despite the existence of only 15 examples, all identified from the Enterobacteriaceae , microcins display diversity in sequence, structure, target cell uptake, cytotoxic mechanism of action and target specificity. Collectively, these features describe some of the unique means nature has contrived for molecules to cross the ‘impermeable’ barrier of the Gram-negative bacterial outer membrane and inflict cytotoxic effects. Microcins appear to be widely dispersed among different species and in different environments, where they function in regulating microbial communities in diverse ways, including through competition. Growing evidence suggests that microcins may be adapted for therapeutic uses such as antimicrobial drugs, microbiome modulators or facilitators of peptide uptake into cells. Advancing our biological, ecological and biochemical understanding of the roles of microcins in bacterial interactions, and learning how to regulate and modify microcin activity, is essential to enable such therapeutic applications.

Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides

“…Microcins are a class of ribosomally produced antimicrobial peptides that are produced predominantly by Enterobacteriaceae and demonstrate activity against a narrow range of related bacteria. The microcins are divided into two classes; class I microcins are post-translationally modified (i.e., RiPPs) and generally <5 kDa in size. , Examples of a subset of class I microcins are discussed in other sections of this review, such as MccB17 (section on LAPs) and MccJ25 (section on lasso peptides). This section will review the known the MOA of all other class I microcins.…”

“…This section will review the known the MOA of all other class I microcins. Class II microcins are larger, ranging from 5 to 10 kDa in size. , Class II microcins are further demarcated into subclasses IIa, which do not contain post-translational modifications, and IIb, which are post-translationally modified through conjugation with a siderophore. , These class IIb siderophore-peptides will be also discussed in this section. Several prior reviews focus on the unmodified subclass IIa microcins that are not RiPPs. ,, …”

“…The microcins are divided into two classes; class I microcins are post-translationally modified (i.e., RiPPs) and generally <5 kDa in size. 37,491 Examples of a subset of class I microcins are discussed in other sections of this review, such as MccB17 (section 3.1 on LAPs) and MccJ25 (section 8.1 on lasso peptides). This section will review the known the MOA of all other class I microcins.…”

“…Class II microcins are larger, ranging from 5 to 10 kDa in size. 37,491 Class II microcins are further demarcated into subclasses IIa, which do not contain posttranslational modifications, and IIb, which are post-translationally modified through conjugation with a siderophore. 37,491 These class IIb siderophore-peptides will be also discussed in this section.…”

“…In turn, the wide variety of natural targets and activities suggests that this class of compounds offers much promise for discovery and engineering of new activities. This review will provide a comprehensive discussion of the MOA of bacterial RiPPs for which such information is available, to complement earlier reviews that focused on specific compound classes or a subset of RiPPs. − The review covers studies reported up to and including 2021.…”