New class of antibiotics that can kill drug-resistant bacteria finally on the horizon?

F Hoffmann-La Roche AG, commonly known as Roche, a Swiss multinational healthcare company, has identified a new class of antibiotics that is active against gram-negative bacteria. This news becomes especially relevant as there has not been a single novel class of antibiotic against such bacteria on the market for the last five decades (since 1968). 

Zosurabalpin, the antibiotic in question, was found to have potent and selective activity against Acinetobacter strains of pneumonia and sepsis, including drug-resistant strains of Carbapenem-resistant A baumannii (CRAB), in mice. 

The medicine is currently being tested on humans under clinical development. Two more molecules belonging to the same family of macrocyclic peptides are also under development. 

CRAB is classified as a priority 1 (critical) pathogen by the World Health Organization (WHO), alongside two other drug-resistant forms of bacteria – Pseudomonas aeruginosa and Enterobacteriaceae. 

Priority pathogens is a catalogue of 12 families of bacteria released by WHO, that pose the greatest threat to human health. According to the 2019 report of the Centers for Disease Control and Prevention on antibiotic resistance, CRAB was responsible for killing 700 people in 2017 and added about $281 million in healthcare costs. 

This bacterium typically causes infections in the blood, urinary tract, lungs and wounds in people who have been cared for in healthcare settings, are very sick, are immunocompromised or require invasive medical devices, like urinary or bloodstream catheters or ventilators.

Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet. 

Through a series of experiments published in the journal Nature on January 3, 2023, Roche and Harvard University scientists described how the new class of antibiotics works by interrupting construction of the bacteria’s outer membrane by targeting the LPS transport machine in Acinetobacter. “New antibiotics directed against the world's highest priority bacteria, like Acinetobacter baumannii, require novel development paths,” said Michael Lobritz, head of infectious diseases, Roche Pharma Research and Early Development (pRED), in an article released by the company. 

In July 2023, researchers from the Delhi-based think tank Centre for Science and Environment published a story in Down To Earth on the current status of antibiotic innovation. With very few antibiotics under development, an analysis of the clinical pipeline of 15 high-earning companies revealed that only a very small percentage (1.3 per cent) of molecules were being developed for treating bacterial infections, while a majority of the molecules were for other disease areas like cancer, immunology, among others. 

Only four companies out of 15 were involved in developing antibacterial candidates, Roche being one of them. This large gap can be attributed to most of the big pharmaceutical companies leaving the antibiotic development space a few decades ago with the complaint that antibiotic innovation is not as rewarding as developing drugs for other lucrative areas like oncology. The issue, however, is that these companies exited the critical antibiotic business even though they are making record profits in other disease areas. 

This is of great concern as with more and more antibiotics becoming ineffective due to the rising issue of antimicrobial resistance (AMR), innovation of new drugs is critical and the need of the hour. 

In 2019, about five million deaths worldwide were estimated to be associated with AMR. It can also impact food security, livelihood, universal health coverage and the attainment of several sustainable development goals. “Antimicrobial resistance is called a ‘silent pandemic’, and over the next 30 years, it is projected to claim more lives than those taken by cancer today,” added Michael in the Roche article. 

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