IISc Team Finds Way to Block A Superbug Transporter

BENGALURU: Researchers from the Indian Institute of Science’s (IISc) Molecular Biophysics Unit (MBU) have found a novel way to block bacteria from flushing out antibiotics which helps them gain drug resistance.
The new finding holds the potential of making existing drugs more effective against drug resistant bacteria or superbugs.

What they’ve essentially done is use a specific antibody found in Indian camels (at the National Research Centre on Camel, Bikaner) to block a transporter that helps bacteria flush out drugs. At present, the team, led by Aravind Penmatsa, assistant professor at MBU, has demonstrated the finding in laboratory conditions.

Bacteria are generally killed by the use of antibiotics. One of the mechanisms they use to gain resistance is called efflux — the process in which bacteria transport compounds such as drugs outside the cell — and transporters play a crucial role in enabling the pathogen to perform this.
That transporters are among major components in the multidrug resistance armoury of bacteria, understanding the molecular architecture of these cell membrane-embedded machines paves the way for designing inhibitors against them, thereby helping in the treatment of diseases caused by these bacteria.
And, according to IISc, in a new study, the researchers “have solved the atomic-resolution structure of one such transporter, NorC, in complex with an Indian camelid antibody (ICab).”

Though transporters are molecular machines that need to shift their conformation (shape/structure) to transport substrates, the team found that the binding of ICab to NorC locked it into a single conformation.
Not only did the transporter get locked in a single state, but the ICab effectively plugged the transporter like a “bottle-cork”, rendering it incapable of interacting with antibacterial compounds (drugs), the researchers said.
“…The process of efflux is very important for bacteria and one of the major strategies that hasn’t yet been explored as a therapeutic mechanism is to develop molecules that can block efflux. If we are able to block transporters that help efflux of certain antibiotics, those drugs will gain efficacy. In some sense, we can enhance the efficacy of available antibiotics if we have blockers of efflux and that’s the potential medical benefit of what we’ve found,” Penmatsa told TOI.

NorC is a transporter found in Staphylococcus aureus — a type of bacteria often found on the skin and in the upper respiratory tract of humans — that
helps provide resistance against broad-spectrum antibiotics like norfloxacin and moxifloxacin.
“These insights will significantly help formulate strategies to counter transporter-mediated antibiotic resistance in pathogenic bacteria, using tools like camelid antibodies. The structure of NorC and the conformation it has been solved in is also the first-of-its-kind, providing a model to study similar drug efflux transporters from other pathogenic bacteria,” IISc added.
The study was primarily funded by the DBT-Wellcome Trust India Alliance and the department of biotechnology.

Source: ToI