Antimicrobials are a cornerstone of modern medicine, enabling treatments that save millions of lives each year. However, their overuse and misuse have led to pathogens developing resistance, rendering many treatments ineffective. This growing issue, known as antimicrobial resistance (AMR), has cast a long shadow over their future.
The consequences are far-reaching. The World Health Organization has named AMR one of the most significant threats to global health, and it’s not hard to see why. Day by day, we have fewer effective antibiotics and increasing resistance. If this continues, we risk entering a post-antibiotic era where minor infections or routine surgeries can become life-threatening.
Our reliance on antibiotics is dangerous. Their versatility and broad target range make them invaluable, but they are indiscriminate blunt tools. These so-called ‘broad-spectrum’ antibiotics not only kill harmful bacteria but also decimate the beneficial microbes that inhabit the gut, collectively referred to as the gut microbiome. This collateral damage dismantles one of our most important natural defences against pathogens: colonisation resistance. Colonisation resistance is the microbiome’s ability to prevent pathogens from growing by competing for resources, engaging in direct bacterial warfare, and promoting the host’s immune response. When antibiotics wipe out beneficial microbes, this protective barrier collapses, leaving the gut vulnerable to reinfection by remaining or external resistant bacteria. Pathogens can then ‘bloom’ beyond the gut unchecked, spreading resistance genes and worsening the AMR crisis. Clearly, we need a different approach – one that protects our microbiota while targeting harmful pathogens.
Narrow-spectrum antibiotics offer a promising solution. These drugs are meant to selectively target harmful bacteria while sparing beneficial microbes. By preserving the gut microbiota, colonisation resistance is maintained, enabling the microbiome to work alongside antibiotics to suppress infections. This synergy also reduces the need for ever more powerful antibiotics.
Despite these advantages, narrow-spectrum antibiotics remain understudied. One reason is diagnostic limitations. Identifying the specific pathogen responsible for an infection currently takes too long, with the few narrow-spectrum antibiotics available designed only to target small groups of pathogens with vulnerabilities unique to each species.
Another issue is that antibiotic development projects often prioritise potency over selectivity. The goal is to identify compounds that rapidly and effectively kill bacteria, but this approach frequently overlooks the importance of sparing beneficial microbes.
Large-scale screening of compounds for antibacterial activity has also hit significant roadblocks. Novel compounds with antibiotic potential are becoming increasingly rare, and researchers are now forced to modify existing antibiotic scaffolds to keep up with AMR. These existing antibiotic classes – such as beta-lactams, fluoroquinolones, and tetracyclines – are all broad-spectrum.
As a result, most antibiotics discovered through these campaigns lack the precision needed to preserve the microbiota. This has left broad-spectrum antibiotics as the default option, despite their drawbacks.
All is not lost – our growing understanding of the microbiome and its connection to health is driving increased research into gut-friendly antibiotics. Approaches that identify and exploit vulnerabilities common to larger groups of pathogens are becoming increasingly common. Additionally, alternative ‘narrow-spectrum’ approaches are emerging, including the use of bacteriophages (viruses that selectivity target bacteria) or bacteriocins (selective protein weapons), which offer promising solutions beyond traditional small-molecule antibiotics.
To address AMR, we must rethink how we design and use these life-saving drugs. Antibiotics should not simply be considered tools to kill bacteria, but rather the consequences of their indiscriminate use should be at the forefront of attention. They can be part of a delicate balance between our bodies and the microbial world. By prioritising narrow-spectrum strategies and leveraging the synergy between antibiotics and the microbiome, we can take a step toward a future where antibiotics remain effective without compromising our natural defences.
The fight against AMR will require innovation, collaboration, and a fundamental shift in perspective – but it’s a fight we can win.
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