Lantibiotic resistance

Abstract

The dramatic rise in the incidence of antibiotic resistance demands that new therapeutic options will have to be developed. One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides. It is interesting that low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Given that there are very few examples of naturally occurring lantibiotic resistance, attempts have been made to deliberately induce resistance phenotypes in order to investigate this phenomenon. Mechanisms that hinder the action of lantibiotics are often innate systems that react to the presence of any cationic peptides/proteins or ones which result from cell well damage, rather than being lantibiotic specific. Such resistance mechanisms often arise due to altered gene regulation following detection of antimicrobials/cell wall damage by sensory proteins at the membrane. This facilitates alterations to the cell wall or changes in the composition of the membrane. Other general forms of resistance include the formation of spores or biofilms, which are a common mechanistic response to many classes of antimicrobials. In rare cases, bacteria have been shown to possess specific antilantibiotic mechanisms. These are often species specific and include the nisin lytic protein nisinase and the phenomenon of immune mimicry.

FIG 1

Mechanisms of lantibiotic resistance which relate to the cell wall and membrane. (A) d-Alanylation of lipoteichoic acids (LTA) and wall teichoic acids (WTA) by the dltABCD operon, which confers a positive charge. (B) Changes in phospholipid composition. (C) Changes in membrane fatty acid composition. (D) Cell wall thickening. (E) Lysine esterification of one of the two hydroxyl groups of phosphatidylglycerol (PG) by Mprf. (F) Gram-negative outer cell membrane containing lipopolysaccharide (LPS).

FIG 2

Two main types of two-component systems (TCSs) are responsible for lantibiotic resistance: the Bce-like TCSs (A) and the Lia-like TCSs (B). The presence of antimicrobials, such as lantibiotics, or the cell damage incurred as a result of their presence causes these TCSs to mediate the transcription of genes whose products confer a resistance phenotype.

FIG 3

In S. aureus, three main TCSs are responsible for lantibiotic/antimicrobial resistance. These include two Bce-like TCSs, BraRS and GraRS, and an Lia-like TCS, VraSR. A coordinated resistance effort results from the actions of these TCSs, causing upregulation of genes whose products alter the composition of the cell wall and membrane and also of genes encoding ABC transporters which expel antimicrobials from the cell.