Why Tackling Antibiotic Tolerance Is Crucial to Combating AMR and Saving Our Existing Antibiotics
Saransh Chaudhary, President, Global Critical Care, Venus Remedies Ltd and CEO, Venus Medicine Research Centre
Antimicrobial resistance (AMR) is one of the greatest global health threats of our time. Drug-resistant infections already claim millions of lives each year. According to the World Health Organization, an estimated 4.95 million deaths in 2019 were associated with bacterial AMR, with 1.27 million directly caused by resistant pathogens. These figures exceed the annual death tolls from HIV/AIDS and malaria and are expected to worsen without urgent intervention.
The Challenge of Developing New Antibiotics
Despite the growing burden of AMR, the development of new antibiotics has been slow. As per the WHO’s 2023 pipeline report, only 51 antibiotics or combinations are currently in clinical development, and most offer little innovation over existing treatments. High research and development costs, limited return on investment, short treatment durations, and stringent regulatory demands have discouraged pharmaceutical companies from investing in new antibiotics.
However, some recent advances offer hope. Zosurabalpin, a macrocyclic peptide antibiotic targeting Acinetobacter baumannii, has shown promise in disrupting bacterial cell membranes by blocking LPS transport—a mechanism not seen in decades. Similarly, LpxH inhibitors, which prevent the early synthesis of lipid A in Gram-negative bacteria, represent another novel mechanism with encouraging preclinical results.
On the regulatory front, Zevtera (ceftobiprole medocaril sodium) was approved by the US FDA in April 2024 for bloodstream and skin infections. In India, Nafithromycin (Miqnaf) was launched for community-acquired pneumonia. Scientists are also exploring lariocidin, a naturally occurring peptide antibiotic with broad-spectrum potential (Science Media Centre España). Additionally, Venus Remedies, in partnership with INFEX Therapeutics, is developing MET-X, a metallo-beta-lactamase (MBL) inhibitor designed to combat resistance to last-line drugs like meropenem.
Still, these breakthroughs are few and years from widespread use. This makes it imperative to preserve the effectiveness of the antibiotics we already have so as to effectively combat AMR.
Global Action Against AMR
Globally, the WHO’s Global Action Plan on AMR, launched in 2015, has shaped strategic responses focused on optimizing antimicrobial use, enhancing surveillance, and promoting sustainable research. By 2024, over 170 countries had adopted National Action Plans. The United Nations has also prioritized AMR through the Quadripartite Alliance, involving WHO, FAO, UNEP, and WOAH.
In India, the National Action Plan on AMR (NAP-AMR), launched in 2017, focuses on surveillance, stewardship, infection prevention, and intersectoral coordination. The Indian Council of Medical Research (ICMR) operates a national AMR surveillance network (NAP-AMR India) and continues to highlight worrying resistance trends, particularly among Gram-negative pathogens.
These efforts are essential to address the growing AMR threat, while supporting innovation in new antibiotics and preserving the efficacy of those already in use.
Yet, amid this global push against resistance, an equally critical but lesser-known challenge continues to undermine treatment outcomes—and that is antibiotic tolerance.
Understanding Antibiotic Tolerance
Unlike resistance, where bacteria grow and multiply in the presence of antibiotics due to genetic mutations or acquired resistance genes, tolerance refers to bacteria surviving antibiotic treatment without growing. These bacteria are metabolically dormant or slow-growing and are not killed efficiently by antibiotics, even though their minimum inhibitory concentration (MIC) remains unchanged.
Tolerant bacteria often appear in biofilms, intracellular niches, or persister cell states, leading to chronic and recurring infections. Unlike resistance, tolerance is non-heritable and reversible, making it an actionable therapeutic target.
Why Tolerance Is a Problem—and a Stepping-Stone to Resistance
Tolerance poses a serious clinical challenge. As antibiotics fail to clear infections entirely, persistent bacteria can survive longer, increasing the probability of mutations and gene transfer that eventually lead to resistance. A study in Science demonstrated that antibiotic tolerance accelerates the evolution of resistance in bacterial populations exposed to repeated antibiotic stress.
Yet, tolerance is less monitored, less diagnosed, and poorly understood in clinical practice—leaving a major blind spot in AMR strategies.
The Silver Lining: Tolerance Can Be Reversed
The key difference between resistance and tolerance lies in their mechanism. While resistance is genetic and permanent, tolerance is largely metabolic and potentially reversible. Emerging research is exploring how metabolic adjuvant therapy can reactivate bacterial metabolism during treatment, enhancing antibiotic effectiveness.
For instance, a study in Nature Microbiology showed that supplementing aminoglycosides with glucose or mannitol re-sensitized tolerant bacteria by restoring proton motive force. Another study in ASM Journal found that adding valine to β-lactam therapy significantly increased efficacy against MRSA. Similarly, combining adenosine monophosphate (AMP) with gentamicin boosted its bacterial killing power by over 100-fold in lab and animal studies
These approaches, once clinically tested and scaled, could reduce the likelihood of treatment failure, recurrent infections, and the evolution of full-blown resistance.
A Holistic Way Forward
If AMR is the visible fire, antibiotic tolerance is the silent smoke smothering treatment outcomes and threatening to ignite new waves of resistance. Yet, unlike resistance, tolerance offers a rare and promising opportunity—because it can be reversed. This distinction makes it a strategic intervention point in the AMR battle.
To capitalise on this, global health agencies and governments must begin integrating antibiotic tolerance more deliberately into their AMR strategies. This includes increasing funding for tolerance-focused research and diagnostics, revising treatment guidelines to account for persistent or recurring infections driven by tolerant bacteria, and promoting awareness of this issue among healthcare practitioners and the public. Additionally, greater scientific investment is needed in exploring scalable metabolic adjuvant therapies that can re-sensitise tolerant bacteria to existing antibiotics.
As we await the arrival of the next generation of drugs, a renewed focus on tolerance could buy us invaluable time and preserve the life-saving antibiotics we already have. The future of antibiotic efficacy may depend not just on what we discover next, but on how we choose to better use and safeguard what’s already in hand.
Entrusted with the mandate of augmenting and monetising the company’s intellectual property wealth and driving key tactical initiatives, Saransh Chaudhary joined Venus Remedies in 2016 as Strategic Board Advisor after completing his undergraduate degree in Accounting & Finance from Cass Business School, London. Two years later, he assumed charge as President of the company’s Global Critical Care division and CEO of Venus Medicine Research Centre (VMRC), its R&D wing. In these roles, he translates priorities into actionable strategies.
