Today, however, they face one of the biggest challenges in modern medicine: antibiotic resistance.
These pathogens have shown resistance to multiple classes of antibiotics, including fluoroquinolones, third-generation cephalosporins, carbapenems and even colistin, a last-resort antibiotic.
As a result, scientists in India and elsewhere are increasingly working on drugs that target the mechanisms of antibiotic resistance rather than simply developing new antibiotics.
In the race against superbugs, the future lies in therapies that disable bacterial resistance rather than simply attacking bacteria themselves.
By restoring the power of existing antibiotics, resistance mechanism-targeted adjuvants could transform the treatment of infectious diseases and provide a much-needed lifeline in the global fight against antimicrobial resistance.
Antibiotics have been considered one of medicine’s great breakthroughs since their discovery in the early 20th Century. Today, however, they face one of the biggest challenges in modern medicine: antibiotic resistance.
Over the years, pathogens have evolved into “superbugs” because of the overuse and misuse of antibiotics, gaining resistance even to the strongest last-line treatments. The consequences are already alarming. More than one million deaths have been directly linked to antimicrobial resistance, while approximately five million deaths are associated with infections caused by resistant bacteria.
A recent report in The Lancet estimated that, if left unchecked, drug-resistant infections could cause a staggering number of deaths by 2050.
India is at the forefront of this growing public health crisis. The country reports some of the highest levels of resistance globally, with increasing cases of multidrug-resistant pathogens such as Escherichia coli, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis.
These pathogens have shown resistance to multiple classes of antibiotics, including fluoroquinolones, third-generation cephalosporins, carbapenems and even colistin, a last-resort antibiotic. The widespread misuse and overuse of antibiotics in both humans and livestock, along with easy access to these medicines, have contributed significantly to the crisis.
India launched its National Action Plan on Antimicrobial Resistance, 2017–2021, in alignment with the World Health Organization’s Global Action Plan. It sought to spread awareness and encourage research and innovation. Yet challenges persist, especially because of limited resources in rural and primary healthcare settings.
This also means that resistance could eventually emerge against even the novel antibiotics now being developed. As a result, scientists in India and elsewhere are increasingly working on drugs that target the mechanisms of antibiotic resistance rather than simply developing new antibiotics.
How superbugs defend themselves
Superbugs such as methicillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae and drug-resistant Mycobacterium tuberculosis have developed strong defences against effective antibiotics.
Many bacteria acquire these resistance traits through horizontal gene transfer, inheriting genetic material from other bacteria, including antibiotic-producing microorganisms that naturally possess such defence mechanisms.
Some bacteria achieve resistance by subtly altering the molecular locks that antibiotics are designed to recognise, making the drugs ineffective. Others produce specialised enzymes that chemically destroy or modify antibiotics before they can act. Still others rely on efflux pumps — molecular machines that actively expel antibiotics from the bacterial cell before they reach effective levels.
Currently, one of the most common ways to tackle resistance is to develop new antibiotics, which may or may not bind to existing antibiotic-binding sites. Designing drugs with scaffolds similar to existing medicines can increase the chances of approval by regulators such as the United States Food and Drug Administration and improve prospects for commercialisation.
But every new antibiotic starts a race against time. Bacteria eventually find ways to evade its effects, forcing scientists to look beyond simply discovering new drugs.
The focus is now shifting towards approaches that neutralise bacterial defence mechanisms and revive the power of existing antibiotics.
Disabling resistance
Bacterial defence mechanisms have become attractive targets for modern drug discovery. Rather than attacking bacteria directly, scientists are developing companion drugs that disable these resistance systems.
By blocking antibiotic-destroying enzymes, preventing changes to the drug’s target or shutting down efflux pumps, these therapies can restore the ability of existing antibiotics to kill even highly resistant bacteria.
One of the earliest successes of this approach came from targeting β-lactamases, enzymes produced by bacteria to destroy β-lactam antibiotics such as penicillins and cephalosporins. Several drug combinations have now received regulatory approval, with ceftazidime-avibactam emerging as one of the most successful examples of antibiotic-adjuvant therapy.
Building on this success, researchers have continued to develop next-generation combinations capable of tackling some of the most difficult-to-treat infections.
A recent advance has come from the Indian pharmaceutical company Wockhardt, with the combination of cefepime and zidebactam, known as Zaynich. This innovation validates the strategy in which cefepime acts as a penicillin-binding protein binder, while zidebactam acts as the β-lactamase inhibitor.
The combination has shown effectiveness even against Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, making it an important milestone for India.
New adjuvant therapies
The success of β-lactamase inhibitors has encouraged scientists to extend this strategy to other bacterial defence mechanisms.
Researchers are now developing adjuvant therapies that target efflux pumps and drug-target-modifying enzymes to restore the effectiveness of antibiotics that have become less useful against multidrug-resistant pathogens.
An exciting example of this emerging approach comes from IIT Bombay, where research led by Prof Ruchi Anand and Prof Pradeepkumar P I has introduced a novel class of antibiotic adjuvants based on DNA aptamers.
Unlike conventional small-molecule inhibitors, these short DNA strands are designed to selectively block a bacterial enzyme responsible for modifying the antibiotic’s target site, a key mechanism of resistance.
When used alongside existing antibiotics, such aptamers may help restore antibiotic susceptibility. This represents a promising addition to the growing arsenal of antibiotic-adjuvant therapies.
In the race against superbugs, the future lies in therapies that disable bacterial resistance rather than simply attacking bacteria themselves. By restoring the power of existing antibiotics, resistance mechanism-targeted adjuvants could transform the treatment of infectious diseases and provide a much-needed lifeline in the global fight against antimicrobial resistance.
Damini Sahu has a PhD in Biochemistry from IIT Bombay. Views expressed are the author’s own and don’t necessarily reflect those of Down To Earth
