The Antibiotic Arms Race: Can Science Stay Ahead of Rapidly Evolving Antibiotic-Resistant Bacteria?

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMFeb 10 2025

Imagine a world where life-saving antibiotics no longer work. That could soon become a reality, as shown by a recent study published in Nature Microbiology.

A team of Hungarian scientists investigated how resistance develops in Gram-negative bacteria, including notorious pathogens such as Escherichia coli and Klebsiella pneumoniae.

They compared the antibiotics currently in use with new candidates and made a concerning observation that bacteria evolve resistance at alarming rates, even to recently developed drugs. This study highlighted the urgent need for innovative strategies to combat antibiotic resistance before we run out of effective treatments.

​​​​​​​Study: ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro. Image Credit: Fahroni/Shutterstok.com

Antibiotic-resistant bacteria

Antibiotic resistance is a growing global health crisis. Bacteria naturally evolve mechanisms to evade antibiotics, but the misuse and overuse of these drugs have accelerated resistance. Gram-negative bacteria, such as E. coli and Pseudomonas aeruginosa, are particularly concerning due to their ability to develop resistance and share resistance genes rapidly.

While new antibiotics are constantly being developed, previous studies have shown that bacteria often outpace these innovations. Research also suggests that resistance emerges through spontaneous mutations or gene transfer between bacteria, often within a few years of a drug’s introduction.

The World Health Organization warns that without immediate action, common infections and minor injuries could once again become life-threatening.

Furthermore, according to the principal investigator Csaba Pál, the focus on developing broad-spectrum antibiotics that target numerous bacteria rather than antibiotics with long-term sustainability has also added to the problem.

About the Study

The present study addressed the critical question of whether new antibiotics fare any better in the ongoing battle against resistance. The researchers analyzed how resistance develops in 40 strains of Gram-negative bacteria, including E. coli, Acinetobacter baumannii, K. pneumoniae, and P. aeruginosa.

They tested 19 antibiotics, including 13 recently developed drugs in clinical trials and six widely used antibiotics. The study employed two key approaches: frequency-of-resistance (FoR) assays and adaptive laboratory evolution (ALE).

In FoR assays, the bacterial cultures were exposed to increasing antibiotic concentrations to estimate the rate of spontaneous resistance mutations, while the ALE experiments subjected the bacteria to prolonged antibiotic exposure, selecting for highly resistant populations over multiple generations.

Additionally, the researchers conducted whole-genome sequencing on 381 laboratory-evolved strains to identify genetic mutations linked to resistance. Functional metagenomic screens were also used to detect mobile resistance genes in bacterial populations.

The study also accounted for genetic background effects by using multiple bacterial strains with different susceptibility profiles. The researchers applied statistical models to assess whether initial antibiotic susceptibility influenced long-term resistance development.

Throughout the experiments, they measured minimum inhibitory concentrations (MICs) to determine how much an antibiotic's effectiveness declined due to bacterial adaptation.

By combining laboratory evolution with genomic analysis, this study aimed to provide a comprehensive look at how bacteria adapt to both existing and new antibiotics, understand the factors that drive resistance, and reveal potential vulnerabilities that could inform future drug development strategies.

Key Findings

The study made an alarming discovery that bacteria developed resistance to both conventional and newly developed antibiotics at similar rates.

Close to 87% of the bacterial populations adapted in the lab reached resistance levels exceeding peak plasma concentrations of the drugs, meaning these antibiotics could become ineffective in real-world scenarios.

The genetic analysis also revealed that resistance mutations frequently targeted key bacterial genes involved in drug transport and metabolism. Some strains showed a high prevalence of loss-of-function mutations that disabled certain pathways, making them more resistant.

Surprisingly, many resistance mutations were already present in natural bacterial populations, suggesting that resistance could emerge rapidly under selective pressure.

For certain antibiotics, resistance evolved within just a few generations. For example, E. coli and A. baumannii rapidly developed significant resistance to SPR-206 and SCH-79797, two promising antibiotic candidates. The study also found considerable overlap in mutational profiles across different antibiotics, indicating that bacteria use common resistance strategies regardless of drug type.

Additionally, mobile resistance genes were detected in both clinical and environmental bacterial samples. These genes can spread between bacteria, further accelerating resistance. The study confirmed that initial antibiotic susceptibility levels influenced the rate at which resistance evolved, highlighting the need to consider genetic background when developing new antibiotics.

Despite these concerning findings, there is hope. The study also identified potential ways to slow resistance evolution. Certain drug combinations and multi-targeting approaches appeared to reduce the likelihood of resistance mutations.

However, none of the tested antibiotics met all the criteria for an ideal resistance-proof drug, highlighting the urgent need for more research in this direction.

Conclusions

To summarize, the study found that bacteria continue to develop resistance even to newly introduced drugs, emphasizing the importance of innovative drug design and responsible antibiotic use.

The findings suggested that without immediate action, the effectiveness of modern medicine is at risk. Future research should focus on designing antibiotics or antibiotic combinations that minimize resistance evolution and implementing policies to curb antibiotic misuse globally.