How to Resist Resistance?

Bacterial resistance has become a common term these days. It refers to the development of
resistance against antibiotics by bacteria. Scientists have been studying this phenomenon for a while
now. Several pathogenic organisms are resisting the action of chemotherapeutics and this has
caused a havoc in the industry. Diseases causing bacteria like Mycobacterium tuberculosis,
Staphylococcus aureus, Pseudomonas aeruginosa and certain species of Enterococci are a major
threat, due to their ability to develop resistance against multiple antibiotics leading to the
emergence of MDR (multiple drug-resistant) and XDR (Extensively drug-resistant) strains. This led to
the study of the cause of resistance.

Julia Williams and Paul Hergenrother referred to bacterial plasmids as the Achilles’ heel of drug
resistance. Plasmids are extrachromosomal DNA present in the bacterium, also referred to mobile
genetic element. Plasmids are capable of horizontal transfer within and across bacterial genera and
species by the process of conjugation. This rapid process can efficiently transfer the gene-pool. Most
frightening modification observed was the transfer of plasmid from VRE (Vancomycin-resistant
Enterococci) to MRSA (Methicillin-resistant Staphylococcus aureus) resulting in practically
untreatable VRSA (Vancomycin-resistant Staphylococcus aureus).

To cope with this mechanism of survival exhibited by bacterial organisms, creative strategies are
being devised. Various ways of inhibiting the process of conjugation, also called COINs (Conjugation
Inhibitors), to avoid the spread of resistance among bacterial species are the prime concern. Several
chemical compounds have already been tested for inhibition although they were later discovered to
be unspecific growth inhibitors. To avoid unspecific inhibitors, target molecules are studied.

In order to develop target drugs, it is essential to know the mechanism of transfer of plasmids from
bacterium to another. It is a two-step process. In the first step, the DNA to be transferred is
mobilized by a set of proteins encoded by the MOB genes. In the second step, the mobilized DNA is
transported across a secretion system, T4SS (type IV secretion system), to be specific. T4SS is a
complex formed by a combination of proteins encoded by a set of genes. In this process, a relaxase
protein is involved, which attracted the eye of the researchers as a target molecule.