Microcins in Enterobacteriaceae: Peptide Antimicrobials in the Eco-Active Intestinal Chemosphere

Abstract

Microcins are low-molecular-weight, ribosomally produced, highly stable, bacterial-inhibitory molecules involved in competitive, and amensalistic interactions between Enterobacteriaceae in the intestine. These interactions take place in a highly complex chemical landscape, the intestinal eco-active chemosphere, composed of chemical substances that positively or negatively influence bacterial growth, including those originated from nutrient uptake, and those produced by the action of the human or animal host and the intestinal microbiome. The contribution of bacteria results from their effect on the host generated molecules, on food and digested food, and organic substances from microbial origin, including from bacterial degradation. Here, we comprehensively review the main chemical substances present in the human intestinal chemosphere, particularly of those having inhibitory effects on microorganisms. With this background, and focusing on Enterobacteriaceae, the most relevant human pathogens from the intestinal microbiota, the microcin's history and classification, mechanisms of action, and mechanisms involved in microcin's immunity (in microcin producers) and resistance (non-producers) are reviewed. Products from the chemosphere likely modulate the ecological effects of microcin activity. Several cross-resistance mechanisms are shared by microcins, colicins, bacteriophages, and some conventional antibiotics, which are expected to produce cross-effects. Double-microcin-producing strains (such as microcins MccM and MccH47) have been successfully used for decades in the control of pathogenic gut organisms. Microcins are associated with successful gut colonization, facilitating translocation and invasion, leading to bacteremia, and urinary tract infections. In fact, Escherichia coli strains from the more invasive phylogroups (e.g., B2) are frequently microcinogenic. A publicly accessible APD3 database http://aps.unmc.edu/AP/ shows particular genes encoding microcins in 34.1% of E. coli strains (mostly MccV, MccM, MccH47, and MccI47), and much less in Shigella and Salmonella (<2%). Some 4.65% of Klebsiella pneumoniae are microcinogenic (mostly with MccE492), and even less in Enterobacter or Citrobacter (mostly MccS). The high frequency and variety of microcins in some Enterobacteriaceae indicate key ecological functions, a notion supported by their dominance in the intestinal microbiota of biosynthetic gene clusters involved in the synthesis of post-translationally modified peptide microcins.

Keywords: Enterobacteriaceae; bacteriocins; chemosphere; colicins; competition; microcins; molecular ecology.

FIGURE 1

The intestinal chemosphere. The chemosphere (light blue layer) is the ensemble of chemical molecules of dietary and environmental origin, released (dark blue vertical arrows) by the physiological or pathological functions of the host or by the complex bacterial communities colonizing the intestine. The chemosphere surrounds the gut microbiota (inner beige circle), composed of a variety of bacterial populations (dark red, brown, and yellow circles). These populations contribute to the chemosphere with chemicals (dark blue angled arrows) that result, probably in combination with other local chemicals, in the growth or inhibition of the same or other populations (red arrows). The chemosphere might have local differentiations with sets of chemicals (hatched circles), but an important part of it is flowing (curved blue arrows). Some components of the microbiota can regulate the secretion of chemicals by the host (gray arrow).

FIGURE 2

Structure of bacterial interactions and the influence of chemosphere. The structure and evolution of the microbiome is based in antagonistic and cooperative interactions in a complex chemical environment, the chemosphere. Top panel, antagonistic (red arrows) and cooperative (blue arrows) interactions among three bacterial populations producing different inhibitors (a–c). (1) The rock-paper-scissors dynamics, assuring coexistence of all three populations, which is enhanced by the cooperative blue bonds. This ensemble of populations cooperates in the inhibition of other competing bacteria (empty circles). (2) Under the influence of chemosphere (green triangle) one of the populations (b) increases in size, producing the collapse of the former equilibrium (3). In (4), because of the maintained coexistence with (a) and the high population size of (b), resistance to (a) might evolve in (b), or genes encoding (a) can be acquired by (b) via horizontal gene transfer, and a new, simpler coexistence might occur (5). Middle panel, the rock-paper-scissors dynamics at a higher hierarchical scale; ensembles of bacterial populations act as single entities able to compete and cooperate with other microbial ensembles. Lower panel, in the center, the dark blue circle represents a bacterial population excreting a “blue” microcin. The concentration of this bacteriocin is high near the producer, but diffusion gives rise to progressively lower concentrations (light blue). White circles, bacteria competing with the blue one, which (vertical line) are killed (red X) at high bacteriocin concentrations, or, at lower ones, prevented to be established (red curved arrow) in this area. In the left oval green circle, diffusion of a local chemosphere component antagonizing the production or effect of microcin, now unable to kill the competitors. In the yellow oval circle at the right, diffusion of a chemosphere component enhancing the effect of the bacteriocin, now able to kill even at very low concentrations.