Lantibiotic Resistance

Abstract

SUMMARY 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.

Efficacy of Lantibiotic Treatment of Staphylococcus aureus-Induced Skin Infections, Monitored byIn VivoBioluminescent Imaging

“…Several lantibiotics are active against antibiotic-resistant pathogens, and their efficacy in treating bacterial infections has been reported in several animal models (11-14, 29, 30). However, resistance to lantibiotics has been described in the literature, and the majority of the mechanisms responsible for resistance involve alterations in the charge and permeability of the cell wall or membrane, respectively (37). Resistance mechanisms include alteration of the cell wall and membrane, such as increases in the positive charge of the cell wall or changes in the phospholipid composition of the cell membrane (37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”

“…Resistance mechanisms include alteration of the cell wall and membrane, such as increases in the positive charge of the cell wall or changes in the phospholipid composition of the cell membrane (37)(38)(39)(40)(41)(42)(43)(44)(45)(46). Other resistance mechanisms include biofilms, spore formation, and, in some cases, specific antilantibiotic mechanisms (37). The development of resistance to lantibiotics, specifically alteration of lipid II, may be reduced due to the unique binding of lantibiotics to the pyrophosphate moiety, which is essential for lipid II function and structure (9,36).…”

Bacterial danger sensing

“…Interbacterial competition has been honed over eons as microbes battle for overlapping niches. Overt antagonism between bacteria is accomplished by diffusible small molecule antibiotics, antimicrobial peptides (AMPs), proteineaceous toxins, and contact-dependent toxin delivery pathways including the type VI secretion system (T6SS) and contact dependent inhibition (CDI), among other mechanisms [6-11]. Given that genes encoding antibacterial factors are virtually universal within bacterial genomes, it would be surprising if bacteria had not evolved generalized cellular programs, i.e., danger sensing pathways, for counteracting them.…”

“…As a result of this common mechanism of action, responses to AMPs across bacterial species also share a number of common features. In contrast to the pathways that detect specific antibiotics discussed earlier in this section, the sensors that perceive AMPs are generally more promiscuous [11, 58]. For example, the aps three-component regulator/sensor system in Staphylococcus spp.…”

“…AMP-sensing pathways in both Gram-negative and Gram-positive species respond by inducing modifications to the cell surface that confer enhanced AMP resistance [11]. The PhoPQ system, for instance, induces the synthesis and incorporation of the positively charged molecule aminoarabinose into lipid A, as described in the previous section [37].…”