New era of antibiotics potentially in sight after more than 50 years

Michael Lobritz recalls the patient that changed the course of his career. At the time an expert on viruses, Michael was part of the team caring for a patient with a tenacious bacterial infection. Despite the considerable resources at the team’s disposal at one of the world’s leading medical centres, no treatment could save the patient’s life. This experience drove Michael to find a solution to the large and growing problem of untreatable bacterial infections - either because there are no medicines targeting them, or because the medicines that once worked, have become ineffective over time.

As the Head of Infectious Diseases at Roche Pharma Research and Early Development (pRED) Michael and his colleagues are now tackling this major public health challenge. “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, according to” says Michael. Effective antibiotics underpin the foundations of modern medicine and are needed to support routine procedures such as surgery or immunosuppressive therapy. However, over time bacteria evolve to avoid being killed by antibiotics, developing resistance to one or more drugs and thus rendering these medicines ineffective. 

Despite the need for antibiotics, and the rise of drug resistance, there has not been a single novel class of antibiotics effective against a class of pathogens known as gram-negative bacteria on the market since 1968.

Roche scientists are applying a wide range of tools to discover novel molecules against some of the most resistant bacteria, including screens of novel chemical libraries, synthetic biology, artificial intelligence and genome mining approaches. Among them are bacteria that top the World Health Organization (WHO) priority pathogen and U.S. Center for Disease Control and Prevention (CDC) urgent threat lists, which are often present in the hospital environment too. There, they can cause severe infections with a high mortality rate, especially in vulnerable patients in intensive care. 

Roche currently has two novel class antibiotics for gram-negative bacterial infections in clinical development - one focused on the treatment of carbapenem-resistant Acinetobacter baumannii, and one focused on the treatment of carbapenem-resistant gram-negative infections.

Developing these potential new medicines is an intense scientific journey, starting by identifying effective molecules, then trying to understand their structure and how they work, and finally making necessary safety tweaks to reduce the toxicity of the molecule for patients. Roche scientists have spent nine years thus far developing potential new antibiotic molecules unlike any developed before, and in doing so have learned more about the fundamental biology of the new antibiotic target.

The new antibiotic targeting carbapenem-resistant Acinetobacter baumannii currently in clinical development not only provides potential hope for patients, but also is potentially an important scientific breakthrough in its own right. In research recently described in back-to-back articles in the journal Nature, Roche scientists and collaborators Dan Kahne, Higgins Professor of Chemistry and Chemical Biology at Harvard Faculty of Arts and Sciences, and Andrew Kruse, Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School,and Unlike many traditional antibiotics, known as broad-spectrum antibiotics, that can kill many different kinds of bacteria — including important, desirable bacteria that help keep us healthy instead of making us ill — the potential new antibiotic is specific to carbapenem-resistant Acinetobacter baumannii. In an unprecedented mode of action, it prevents the bacterium from properly constructing its protective membrane.

The Kahne lab has shown that the Roche clinical candidate inhibits the LptB2FGC complex, the machinery that assembles the outer membrane of gram-negative bacteria. The Kahne and Kruse labs have used cryo-EM to determine the structures of several co-complexes, providing key structural and biochemical information that has shed light on the mechanism of target inhibition.

Importantly, the new molecule will help uncover new biology about the construction of bacterial membranes. However, the ultimate goal is to develop a potential new medicine that will effectively kill what was once an uncommon bacterium and is now one of the biggest infectious disease challenges to public health.

Roche is highly engaged across the public-private spectrum to address the challenges of antimicrobial resistance (AMR). To complement in-house research, Roche engages in local partnerships as well as academic collaborations to advance basic science knowledge. Further, Roche is a sponsor of the AMR Action Fund, initiated by the International Federation of Pharmaceutical Manufacturers and Associations with the aim to bring new AMR countermeasures to patients. Importantly, Roche has also joined forces in a private-public-partnership* with the Biomedical Advanced Research and Development Authority (BARDA)*, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, to advance the development of medicines for infectious diseases.

The role of diagnostics is also crucial in the fight against AMR.  Without a better understanding of the bacterial infection, critically ill patients infected with drug-resistant bacteria may receive standard-of-care antibiotics that are ineffective. On the other side of the problem, patients without serious bacterial infections are often overtreated with antibiotics, driving additional antibiotic resistance. This is a major cause of antibiotic resistance and puts the world’s population at risk.

Using rapid molecular diagnostics, it will be possible to identify drug-resistant infections in hours instead of days, thus saving the patient from unnecessary exposure to ineffective drugs while waiting for test results. It also means patients without drug-resistant infections will be able to receive the right antibiotics at the right time, which may improve patient outcomes, and also potentially prevent the further spread of antibiotic resistance.

Roche has a long history of developing anti-infectives. Several of them are on theand have collectively saved millions of lives. And they still do today. Roche is investing both in research and development of antibiotics against some of the most serious infections as well as in diagnostic solutions to tackle antibiotic resistance. Roche is committed to bringing to patients novel medicines and diagnostics that can provide long-term solutions to the crisis. With the latest research findings, scientists have made great strides in this direction. “We are driven by the needs of patients to create the tools to fight infections, both now and in the future,” adds Kenneth.

*agreement HHSO100201600038C