Combatting Antimicrobial Resistance: Researchers Test More Than 10,000 Drug Pairings

A scientific depiction reveals that antimicrobial medications, which focus on different aspects of bacterial cells, can mutually affect their efficacy. Credit goes to Isabel Romero Calvo and Elisabetta Cacace from EMBL.

In a comprehensive research endeavor, scientists from EMBL have examined over 10,000 pharmaceutical combinations against key pathogenic bacteria that exhibit antimicrobial resistance and are implicated in human mortality.

Antimicrobial resistance, the phenomenon where infectious agents become resilient to antibiotic treatments, remains a significant and urgent global health concern. Research from 2022 demonstrated that nearly five million deaths in 2019 could be attributed to bacteria that are resistant to antibiotics; more than one million of these deaths were directly due to antimicrobial resistance.

In a recent research effort, the Typas Group at EMBL Heidelberg has methodically assessed the effectiveness of over 10,000 pharmaceutical pairings against prevalent multidrug-resistant bacteria.

Elisabetta Cacace, the inaugural author of the study and a former doctoral student in the Typas Group, noted, “While prior studies have explored specific drug pairings, especially those frequently co-prescribed in medical settings, a systematic understanding of how different classes of antibiotics, or mixtures of antibiotics and non-antibiotic drugs, impact bacterial physiology has been lacking.”

Now a postdoctoral researcher at ETH Zürich, Cacace, who also holds a medical degree, has been deeply involved in studying antimicrobial resistance throughout her career. While part of the Typas Group, which focuses on high-throughput techniques for examining bacterial interactions and physiology, her research pivoted towards understanding the mutual effects of antibiotics on their respective cellular targets.

Different antibiotics interact with varying cellular structures or processes within bacteria. These drugs can either synergize, enhancing their collective potency beyond individual effects, or antagonize, where one drug inhibits the efficacy of another. Such antagonistic interactions can be strategically used to minimize the unintended impact of antibiotics on beneficial gut microbes.

In a preceding study, the Typas Group had examined drug combinations against Gram-negative bacteria, which include dangerous antimicrobial-resistant pathogens like E. coli, Salmonella enterica, and Pseudomonas aeruginosa. However, many fatal antimicrobial-resistant bacteria are also Gram-positive, such as methicillin-resistant Staphylococcus aureus (MRSA), which leads to hundreds of thousands of deaths annually. These bacteria differ in cell wall structure from Gram-negative bacteria, affecting drug activity and efficacy.

For the present research, sophisticated robotic setups were used to simultaneously evaluate hundreds of antibiotic and non-antibiotic drug combinations across varying dosages on three representative Gram-positive bacterial species—Bacillus subtilis, Staphylococcus aureus, and Streptococcus pneumoniae. The study included over 8,000 combinations of 65 distinct antibiotics from all major classes, as well as over 2,500 pairings of antibiotic and non-antibiotic drugs, given the increasing prevalence of polypharmacy—the concurrent usage of multiple medications.

By employing this method, the researchers identified over a thousand synergistic and antagonistic interactions, the effects of which were highly species-specific and even strain-specific. These findings diverged from those observed in their previous study on Gram-negative bacteria. Some results were also validated in vivo by infecting moth larvae with pathogens and assessing the efficacy of specific drug combinations in aiding recovery.

The complete database of interactions has been made publicly accessible for scientists to review, investigate, and search for new synergistic or antagonistic interactions.

“The sheer scale of this study makes it exceptional. The data set is so extensive that it will likely provide fodder for hypothesis generation for years,” remarked Cacace. “The study is also enlightening from a systems biology standpoint, unveiling drug interactions targeting cellular processes previously unknown.”

Nassos Typas, the senior author of the study and EMBL Group Leader, concluded, “We are in a period where innovative approaches to counter antimicrobial resistance are critically needed. The development of new antibiotics is both technically complex and resource-intensive. The systematic profiling of drug interactions we’ve conducted offers an avenue for alternative treatment strategies for bacterial infections.”

Reference: “Systematic analysis of drug combinations against Gram-positive bacteria” by Elisabetta Cacace et al., published on 28 September 2023 in Nature Microbiology.
DOI: 10.1038/s41564-023-01486-9

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More about Antimicrobial Resistance

• EMBL Heidelberg
• Typas Group Research
• Antimicrobial Resistance Global Report
• Systematic Analysis of Drug Combinations Against Gram-Positive Bacteria – Nature Microbiology
• Polypharmacy in Modern Medicine
• ETH Zürich Research
• Global Health Challenges
• Staphylococcus aureus Infections
• Systems Biology Research
• Gram-Negative vs. Gram-Positive Bacteria