A groundbreaking discovery has been made in the fight against drug-resistant bacteria with the development of a novel antibiotic that can overcome the defenses of one of the most challenging bacterial species, carbapenem-resistant Acinetobacter baumannii (CRAB).

The newly designed drug, called zosurabalpin, takes a unique approach in targeting and eliminating CRAB, which has shown resistance to most existing antibiotics. Unlike previous antibacterial drugs, zosurabalpin utilizes a highly targeted attack strategy that is specific to the CRAB species, rendering its existing defenses ineffective.

Researchers from Roche Pharma Research and Early Development in Basel, Switzerland, and Harvard University have collaborated to develop this groundbreaking antibiotic. Their findings, published in the journal Nature, describe the discovery of zosurabalpin and its mechanism of action. The drug is currently undergoing early-stage safety trials in humans.

CRAB has been classified as an "urgent" threat due to its widespread resistance to antibiotics. It causes various infections, such as blood, urinary tract, lung, and wound infections, predominantly in healthcare settings. The bacterium poses a significant risk to individuals with weakened immune systems or those requiring catheters or ventilators.

The development of zosurabalpin is particularly significant for countering CRAB, as it belongs to the gram-negative bacteria group. Finding effective antibiotics that target gram-negative bacteria has been a challenge for over 50 years, primarily due to the difficulty in penetrating their outer membranes and staying within the bacteria long enough to combat infections.

The research team set out to find new types of antibiotics by extensively screening a library of approximately 45,000 chemical compounds, including synthetic compounds with unique properties not typically found in standard libraries. From this screening, they identified a compound that could be modified to create zosurabalpin.

Initial tests of zosurabalpin showed promising results against various strains of A. baumannii with different levels of resistance, while remaining ineffective against other disease-causing bacteria. The compound was further enhanced to increase potency and successfully cleared infections in mice and rats.

During the drug development process, safety concerns were also addressed. Although zosurabalpin proved effective against A. baumannii, it reacted with lipids in the animals' blood, causing harm. Scientists overcame this issue by adjusting the compound's electrical charge.

Exploring the mechanism of action, researchers discovered that zosurabalpin disrupts key machinery involved in building CRAB's outer membrane. By interfering with the transportation of lipopolysaccharide (LPS), a crucial component in membrane formation, zosurabalpin effectively cripples CRAB. Importantly, the drug was found to be highly specific to A. baumannii due to unique molecular differences, preventing it from binding to other bacterial species.

The narrow targeting of zosurabalpin offers potential advantages in preserving the gut microbiome and minimizing disturbance to beneficial bacteria in the body. Unlike broad-spectrum antibiotics, which can indiscriminately impact the gut microbiome, the specific targeting of zosurabalpin reduces the pressure on non-targeted bacteria to develop resistance.

However, researchers acknowledge the possibility of CRAB evolving new resistance strategies in the future. Yet, they believe that by starting with a new drug class, they are not at a disadvantage, as bacteria may develop vulnerabilities to other antibiotics or lose the ability to cause disease. Further studies will be conducted to investigate these aspects during subsequent trials.

Ongoing safety trials of zosurabalpin in healthy volunteers are currently underway. Beyond zosurabalpin, the development of this innovative antibiotic raises the possibility of targeting LPS as a potential strategy for future antibiotics against other gram-negative bacteria.

Overall, this breakthrough brings hope in the battle against drug-resistant bacteria and offers a glimmer of possibility for a new class of antibiotics capable of combating highly resistant species like CRAB.