Giving teeth to antibiotics

The next time an antibiotic you've taken successfully fights off an infection, you may want to acknowledge the contribution of Hussain Bhukya, a Research Scholar at the IITB-Monash Research Academy.

Most of the antibiotics available today in the market are naturally occurring compounds in many of the bacterial species; they were isolated and screened extensively for treatment/cure for several infectious diseases in humans. Modern antibiotics have significantly enhanced the quality and expectancy of the life of people around the world. The lead molecules in drug discovery and development are from nature's molecular diversity. More than 70% of the antibiotics isolated from bacteria are from Streptomyces species. Arguably the largest antibiotic-producing genus, this species is the source for many antibacterial, antifungal, and antiparasitic drugs.

(Left) Streptomyces producing pigmented antibiotics. (Centre) Capsules. (Right) How antibiotics bind and alter the biological function of their target protein.
Picture Credit: The website of the Washington post

Using antibiotics to treat infections is like a cat and mouse game. With infections every now and then occasionally getting the better of antibiotics there is a continuous demand for medicinally useful antibiotics to treat bacterial infections that are resistant to the current antibiotics.

And this is where Bhukya initiated this project under the guidance of Prof. Ruchi Anand at IIT Bombay. Prof. Anand's laboratory is trying to make a difference by working on various aspects of combating antibiotic resistance. In acquiring resistance from environmental threats, bacteria have developed a well-established communicating system in which they employ their secondary metabolites as chemical signaling molecules. Understanding the mechanism of how the bacteria overcomes these environmental threats by altering their gene expression, thereby responding to the cell-to-cell signaling system, opens up an extremely significant paradigm of extracting medically useful antibiotics.

A doctor treating scarlet fever (or scarlatina), a bacterial infection caused by group A
Streptococcus or "group A strep".
Picture Credit: The website of centers for disease control and prevention

It has been well established that the mechanism of antibiotic production in bacteria is overseen by transcriptional regulatory proteins. These proteins respond to inter- as well as intra-cellular signaling molecules in a synchronized manner to trigger antibiotic production. The communication between chemically signaling molecules plays a vital role in the antibiotic biosynthesis and they are very specific to their target proteins (mostly transcription regulators). So far, the identity of these signaling molecules has not been completely explored.

Currently, under the guidance of Dr. Milton Hearn, Dr. Reinhard Boysen and Dr. Anand, Bhukya is specifically attempting to identify and characterize the chemical signaling molecules that are involved in regulating antibiotic production in the Streptomyces species. He is pursuing some of the transcription factors (CprA, CprB and ScbR) and trying to find the pathways regulated by these proteins along with the identity of the small signaling molecules regulating their action.

The image to the left represents the overall X-ray crystallographic picture of how CprB (transcription factor) binds to DNA and represses the antibiotic production in Streptomyces coelicolor. The arrows show the DNA and ligand binding domains of CprB. The mass spectrum to the right is for the chemical signaling molecules extracted from the growth medium of Steptomyces coelicolor (Study by Bhukya, et al). The small molecule shown in the spectra is the signaling molecule for ScbR (Study by Hsiao, et al).
Picture Credit: Hussain

Established in 2008, the IITB-Monash Research Academy is an important collaboration between Australia and India. It offers graduate research scholars the opportunity to study for a dually-badged PhD from both IIT Bombay in India and Monash University in Australia, spending time in both countries over the course of their research. "I am excited about the potential that the IITB-Monash Research Academy has. I anticipate that, over time, as the 'Academy' begins to grow, it will make substantial contributions particularly in the area of industry-academia linkages. Already, just seven years after commencement, the 'Academy' has built long-term partnerships with many leading industry partners in India and Australia," says Prof Mohan Krishnamoorthy, CEO, IITB-Monash Research Academy.

Says Bhukya, "As the pathogenic bacteria are becoming resistant to the existing antibiotics, there is a constant need for modern antibiotics. In spite of several harsh conditions in the environment, a few bacterial species survive by controlled alteration of their gene expression and antibiotic production. We are interested in understanding how our protein of interest (CprA, CprB and ScbR), with the help of small chemical signaling molecules, regulates antibiotic production in Streptomyces coelicolor." "Nature adopts a beautiful and ultimate selection process in which only the fittest survives. I'm equally fascinated by both science and nature, and feel I'm on a perfect platform to make a difference."

Research scholar: Hussain Bhukya, IITB-Monash Research Academy

Project title: Investigation of quorum sensing molecules in the regulation of antibiotic production in Streptomyces coelicolor

Supervisors: Prof. Ruchi Anand, Prof. Milton T. W. Hearn and Dr. Reinhard I. Boysen

Contact details: hussain.gps@iitb.ac.in

Contact research@iitbmonash.org for more information on this, and other projects.

The above story was written by Mr Krishna Warrier based on inputs from the research student and IITB-Monash Research Academy. Copyright IITB-Monash Research Academy.