Innovation and collaboration in drug development helps combat antibiotic resistance

Antibiotic resistance is a silent pandemic. It advances gradually without immediate or dramatic visible signs, rendering it less conspicuous than other health crises. However, antibiotic resistance is a serious problem facing the entire global community. Resistance builds up over time as bacteria evolve and gain the ability to survive in the face of treatments that once worked. This gradual development means the impact of antibiotic resistance can go unnoticed until doctors and patients run out of options — facing infections that are more severe and harder to treat. There is an urgent need for innovative solutions and global cooperation to address antibiotic resistance. St. Jude scientists are developing solutions to this hidden but formidable health care threat.

The silent crisis of antibiotic resistance 

At the heart of this silent pandemic are antibiotics — a type of medication used to treat infections caused by bacteria. Antibiotics are the most important type of antibacterial agent and are widely used in treating and preventing such infections. Antibiotic resistance occurs when bacteria utilize existing or newly evolved mechanisms that protect them from these drugs. This resistance arises primarily from the overuse and misuse of antibiotics in human and veterinary medicine. Inappropriate prescribing, such as to treat nonbacterial illnesses where antibiotics are ineffective and incomplete courses of treatment that do not eradicate all bacteria, further contribute to resistance. 

A growing public health concern, resistant bacteria spread between individuals and environments, leading to widespread outbreaks that are difficult to manage and eradicate. This issue is particularly prevalent in nosocomial infections, which are acquired in hospital settings where sick patients, often in close quarters and with compromised immune systems, create an ideal environment for the spread of resistant strains. These infections lead to longer hospital stays, more complex and costly treatments, and heightened medical risks, especially for patients undergoing therapy or dealing with other underlying illnesses that compromise their immune systems. Effectively managing infections is crucial for individuals with chronic illnesses or autoimmune conditions, as drug-resistant infections can be life-threatening.

“There are three fundamental issues with the severely immunocompromised patient population,” explains Jason Rosch, PhD, St. Jude Department of Host-Microbe Interactions. “First, the lack of an immune system can allow for different resistance mechanisms to potentially emerge, so it’s almost like a ‘canary in a coal mine’ for drug resistance. Next, the immune system is not robustly present, so we must rely on the drugs to do the heavy lifting, unlike in healthy individuals. Lastly, they are susceptible to atypical pathogens that we rarely see cause infections in the general population.” 

Bringing research to the frontlines at St. Jude 

Rosch’s research focuses on understanding the role of high-risk hosts, such as immunocompromised patients, in susceptibility to infections and developing antibiotic resistance. Additionally, he investigates host-pathogen interactions and the mechanisms underlying antibiotic resistance. Researchers hope to identify methodologies to combat the issue by understanding how bacteria develop resistance. 

“We use advanced genetic tools to interrogate bacterial pathogens to understand pathways that lead to resistance to the antibiotic and potentially resensitize them,” Rosch says.

Recent work by Rosch’s lab, published in Cell Chemical Biology, focused on antibiotic and vaccination pressures on Streptococcus pneumoniae populations, a multi-drug resistant human pathogen that develops resistance quickly.

“There are ways that we could take resistant bacteria, identify their vulnerabilities through genetic analysis and develop strategies to target and counteract their resistance mechanisms or discover new pathways that can be targeted to address resistant strains effectively,” said Rosch.

The evolution of antibiotic resistance 

Antibiotic use and misuse create selective pressure that favors the survival of bacteria capable of escaping these drugs. These resistant strains then proliferate and spread, outpacing their nonresistant counterparts. 

Peijun Ma, PhD, St. Jude Department of Pharmacy and Pharmaceutical Sciences, uses single-cell RNA sequencing to analyze the evolutionary processes of bacterial resistance at the single-cell level. By examining the transcriptional heterogeneity in bacterial populations, she can identify these rare subpopulations with a higher propensity to acquire resistance and gradually become dominant. 

She explains, “Since bacterial populations are not uniform — some cells have a higher likelihood to acquire resistance than others — single-cell analysis enables us to distinguish between these two types of cells. This distinction helps us identify unique transcriptional programs associated with resistance acquisition, providing deeper insights into how bacteria develop and propagate resistance.” 

By identifying genetic markers that aid bacteria in developing antibiotic resistance, therapies can be developed to treat infections associated with antibiotic resistance. 

Advancing drug development to combat antibiotic resistance

The simplest, most immediate solution to antibiotic resistance is to develop new drugs. Unfortunately, the development of new antibiotics has not kept pace with the emergence of resistant bacterial strains, leaving clinicians with fewer effective options. The void of discovery for new antibiotics has persisted for several decades, with significant gaps in the development pipeline stretching back to the early 1980s.

“New antibiotics are introduced to the market, but bacteria often evolve resistance to these drugs relatively quickly. While there are strategies to manage and control resistant infections, effectively implementing and maintaining these measures remains a significant challenge,” explained Ma. 

Richard Lee, PhD, St. Jude Department of Chemical Biology and Therapeutics, specializes in designing, synthesizing and developing novel drugs and other therapeutic approaches for treating antibiotic-resistant infections. “We've been developing new therapies by investigating bacterial resistance mechanisms and optimizing drug delivery into the bacteria,” he says.

Lee’s lab is one of the few worldwide to specialize in synthesizing complex semi-synthetic antibiotics. In an extensive review recently published in Nature, Lee and his colleagues explore the sophisticated action mechanisms nature uses to target bacteria in some of the most effective antibiotics, aiming to draw inspiration for designing new antimicrobial agents that could play a role against multidrug-resistant bacterial infections. 

“We draw insights from nature, such as natural products, analyze the strengths and limitations of both synthetic and natural product approaches, and then integrate these findings with chemical knowledge to identify new opportunities through structural biology and screening,” explained Lee. “There are numerous approaches to improving compounds, and by integrating these methods, we can more effectively begin to tackle the challenges associated with antibiotic resistance. It’s a constant battle against evolution, as we’re not just working against a single bacterium, but billions of them.”

A collaboration toward innovative solutions

It cannot be denied that new drugs are desperately needed to treat resistant bacterial infections. Through many collaborative efforts, St. Jude is at the forefront of new drug development efforts to develop novel treatment strategies for patients. 

“At St. Jude, it’s incredibly rewarding to identify intriguing targets because we have the opportunity to collaborate closely with our colleagues in Chemical Biology and Therapeutics,” said Rosch. “We can reach out and say, ‘We’ve identified a promising target — can we explore its potential as a druggable target?’ They assist us with fundamental biology and biochemistry, and, together, we work on finding inhibitors and advancing these discoveries toward actionable insights and potential drug development.”

To address the ongoing challenges of antibiotic resistance, Ma says, “We need to develop innovative strategies to manage bacterial infections. Instead of aiming to eradicate these pathogens, we might focus on alternative approaches, such as inhibiting their ability to evolve resistance. By preventing bacteria from developing resistance mechanisms, we can improve the effectiveness of existing treatments and better control infections.”