Inhibiting conjugation as a tool in the fight against antibiotic resistance

Abstract

Antibiotic resistance, especially in gram‐negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid‐encoded conjugation system and the host‐encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.

Comprehensive in silico survey of the Mycolicibacterium mobilome reveals an as yet underexplored diversity

“…In bacteria, plasmids are one of the main vectors for the spread of antibiotic resistance genes, and represent an example of bacterial adaptation in response to selective pressures [86][87][88][89][90].…”

Protein Dynamics in F-like Bacterial Conjugation

“…The TraG homolog VirB8 has a proposed druggable site at a PPI interface ( Section 4.2 ), however small molecule ligands proven to be optimal for disrupting conjugation in Ti plasmid donors show poor inhibitory action in the related TraE from pKM101 [ 2 , 117 , 162 ]. Exploiting the Fin-TraJ expression system through the use of activators or inhibitors would be highly effective (discussed in Section 2 ), however drugs targeting these biomolecules are likely to suffer from pronounced plasmid specificity [ 163 ]. The ATPase TrwD from the R388 plasmid has been inhibited through the administration of unsaturated fatty acids (UFAs) such as linoleic acid, and 2-hexadecanoic acid; docking simulations have provided context for further optimization as the UFAs bind non-competitively [ 164 ].…”

Interference plasmids and their use in combating bacterial resistance

“…Since it is widely recognized that the spreading of antibiotic resistance in bacteria is accomplished mainly by means of HGT, scientists are focused on studying the mechanism of HGT [21] and on searching for methods that prevent HGT in bacterial colonies [22]. Research is being actively conducted in the following areas: plasmid curing compounds, using phages for plasmid curing, plasmid curing by CRISPR/Cas system, and incompatibility-based plasmid curing systems.…”