A hunt for novel antibiotic targets

Keerthi Raj B S

As the problem of antibiotic resistance mounts worldwide, there is a pressing need for identifying and testing novel drug targets. Recently, a team of Indian researchers has identified a protein pathway in an antibiotic-resistant bacterial strain which can be targeted using a small molecule to effectively kill the bacteria.

Scanning Electron Micrograph showing the interaction between Staphylococcus aureus (green) and a human white cell
Scanning Electron Micrograph showing the interaction between Staphylococcus aureus (green) and a human white cell   (Photo: NIAID, Public Domain)

In a recent study, researchers led by Harinath Chakrapani and Siddhesh Kamat at the Indian Institute of Science Education and Research (IISER), Pune, and Sidharth Chopra at the Central Drug Research Institute (CSIR-CDRI), Lucknow, have identified druggable targets (“vulnerabilities”) in an antibiotic-resistant strain of Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is a species of bacteria commonly found on human skin and mucosal membranes (such as the inside of the nose). However, if allowed to enter the bloodstream or internal tissues, it can cause serious or fatal infections such as pneumonia, endocarditis (heart valve infection leading to heart failure or stroke), osteomyelitis (bone infection) etc. 

As reported by the World Health Organization (WHO), drug-resistant pathogens might cause up to 10 million deaths a year in India by 2050, a number which is among the highest in the world. Bacteria can become resistant to antibiotics in several ways. They can neutralize’ an antibiotic, making it harmless. They can pump an antibiotic out of the cell before it causes any harm. They can also change their outer structure such that the antibiotic has no way of attaching to them. 

S. aureus can readily become resistant to antibiotics, limiting treatment options. In the present study, researchers have identified proteins in S. aureus that can be targeted to kill the antibiotic-resistant strain of the bacteria. The researchers have also developed a novel small molecule that can act on the identified protein targets to destroy the bacteria.

The new molecule, an indole-based quinone epoxide (IND-QE), can cross the bacterial cell barrier and destroy the bacteria by inhibiting the function of MarR proteins, which are essential for the growth and survival of S. aureus. The indole moiety in IND-QE increases its permeability into bacterial cells. The epoxy group ensures the molecule’s reactivity with the target proteins. 

Expertise in various areas is necessary to address an issue as complex as antibiotic resistance. IND-QE compounds were synthesised at Chakrapani’s laboratory at IISER Pune, while Chopra’s team at CSIR-CDRI screened the compounds against a panel of pathogens. This was followed by experiments to identify and validate the protein targets of these compounds at Kamat’s laboratory. We had to eliminate a few hundreds of possible targets to discover that the MarR family of proteins could be targeted to effectively kill the bacteria,” says Chopra.

New antibiotics are usually discovered from natural products such as fungal or plant extracts, or from large chemical libraries, which are a series of stored chemicals. The novelty of the study is in its attempt to establish a relatively less-explored process of antibiotic discovery,” says Nishad Matange, IISER Pune, a researcher who specializes in antibiotic resistance, who was not associated with this study. IND-QE is an interesting molecule that could prove valuable in the development of new antibacterial agents,” he adds.

Some people predict that it is only a matter of time that we have infections that are not treatable. It is, therefore, possible that routine infections may become fatal,” says Chakrapani, explaining his motivation behind studying antibiotic resistance. The protein targets identified in this study can provide an impetus for further drug discovery and screening.

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