Combating the “Silent Pandemic”: A Conversation with Dr. Michael Lobritz, Global Head Infectious Diseases Therapeutic Area, Roche Pharma Research & Early Development

As the world continues to grapple with the growing threat of antimicrobial resistance (AMR)—often referred to as the “silent pandemic”—Roche stands at the forefront of the fight. With a rich history in both pharmaceuticals and diagnostics, Roche is uniquely positioned to tackle AMR from multiple angles. We spoke with Dr. Michael Lobritz, Global Head of Infectious Diseases Therapeutic Area at Roche Pharma Research & Early Development (pRED), where he leads discovery and early clinical development for Roche’s antibiotics portfolio. Dr. Lobritz’s insights highlight Roche’s leadership and innovation in both pharmaceuticals and diagnostics, including breakthroughs like the development of zosurabalpin, as recently published in Nature.

Thank you for joining us today, Michael. With Roche’s leadership in pharmaceuticals and diagnostics, how does this uniquely position the company to address AMR? Could you share some of the specific innovations or initiatives Roche is currently pursuing?

Michael Lobritz: The Roche group is deeply committed to the infectious diseases field and is uniquely positioned to address antimicrobial resistance (AMR) by investing in both new antibiotics and the diagnostic technologies that complement them. Equally important is our collaboration with external partners to ensure a coordinated global response and meaningful action against AMR.

One area I’d like to highlight is our work in antibacterials R&D within our pharma division. While there is a need for a wide range of antibacterial technologies, we choose to focus on developing novel molecules or chemotypes with highly differentiated mechanisms of action. Our goal is to create agents that are not compromised by the existing resistance accumulated in today’s classes of antibiotics.

Roche has a pipeline of innovative agents in preclinical and early clinical development. Two notable examples currently in clinical trials include zosurabalpin, a narrow-spectrum agent coming from a novel chemical class and addressing a novel target designed to treat carbapenem-resistant Acinetobacter baumannii, and an agent developed by our Genentech team in San Francisco targeting bacterial signal peptidase (LepB), which is also a novel chemical class.

We created zosurabalpin within our Roche Pharma group in Basel starting over a decade ago through a screen of 45,000 distinct macrocyclic peptides from the Tranzyme library. This led to a molecule with a novel mechanism of action affecting the bacterial lipopolysaccharide (LPS) transporter. Working with our partners at Harvard University, we discovered that this compound uniquely binds to both the transporter and the natural substrate, LPS, simultaneously, inhibiting LPS transport to the bacterial outer membrane. This novel mechanism holds promise to overcome pre-existing resistance in an important bacterial pathogen. Overall, we’re hopeful that these innovations will lead to new medicines capable of addressing AMR in a meaningful way.

It sounds like Roche is specifically pursuing new mechanisms of action and chemotypes. Could you tell us more about that focus?

Michael Lobritz: That’s correct. Our focus is specifically on novel chemical classes. In considering our contribution to AMR, we choose to work in this highly innovative space. Over the past century, antibiotics have been transformative for modern medical care, enabling us to manage bacterial infections successfully. I don’t wish to underplay the critical value that derivatives of existing antibiotic classes also play in delivering clinical value to patients. Indeed, the current arsenal of over a hundred antibiotics is primarily built on a small number of core chemical scaffolds, such as the quinolones, beta-lactams, and aminoglycosides.

Our goal is to discover new chemical classes that can serve as foundations for further derivatization, optimizing pharmacokinetics, safety, and spectrum of activity in the future. Ideally, identifying even a few new classes could fuel a long-term pipeline, laying the groundwork not only for today’s antibiotics but for the medicines needed in the coming century.

Developing effective therapies for these diseases has proven challenging. Why do you think this is?

Michael Lobritz: There are several reasons why discovering new molecules has been challenging. One key factor is the unique biological and physical chemical properties of bacteria. Since the post-genomic era, sequencing bacteria has allowed us to identify the essential genes they need for survival—on average around 300 out of 3,000 genes. In theory, if we target these essential proteins, we should be able to kill the bacteria. However, many efforts in this direction have resulted in molecules that bind tightly to these enzymes but fail to kill bacteria in whole-cell assays, primarily due to the complexities of the bacterial outer membrane.

Unlike human cells, gram-negative bacteria have a second membrane. This outer membrane is especially complex and serves as a protective barrier that regulates what chemicals can enter and exit, enhancing the bacteria’s resilience in the human body and in diverse environments. This outer membrane prevents dessication and plays a key role in survival, but it also makes it extremely difficult for antibiotic-like molecules to penetrate and reach their targets. We are still only beginning to understand how to overcome this barrier and develop compounds with the permeability needed to enter the cell and effectively bind to targets. This formidable outer membrane poses a significant scientific challenge in identifying new chemotypes with both high affinity for targets and the ability to permeate bacterial defenses.

Given these challenges, how does Roche approach translation?

Michael Lobritz: Good question. Discovering new chemotypes is challenging, but translating them to effective human treatments is equally difficult. I would highlight two major barriers: safety and pharmacokinetics.

First, safety is crucial. For instance, penicillin is exceptionally safe, but replicating that safety in new chemical classes is tough. Dose is a big factor—many antibiotics require gram-level doses to be effective, unlike other drugs that can work on milligram scales. To effectively reach and eliminate bacteria in tough areas like the lungs or bones, high doses are often needed, which raises the risk of off-target effects and associated safety issues.

Second, pharmacokinetics: in test tubes, the drug simply needs to kill bacteria at a set concentration, with no distribution or elimination factors. But in humans, the drug must reach infection sites, have the right tissue distribution, half-life, and solubility. Tuning these properties is a complex process that takes time and effort to turn a promising lab molecule into a viable human medicine.

As a leader in diagnostics, how is Roche advancing technology to support early detection and resistance identification?

Michael Lobritz: At Roche, we believe that investments in innovative diagnostics must go hand in hand with the development of new antimicrobials. If significant resources are devoted to bringing a new drug to market without a complementary diagnostic to ensure its proper use, that drug could quickly become ineffective due to resistance. This, from our perspective, is a tragic waste.

To this end, Roche is committed to supporting the fight against AMR with a robust diagnostics portfolio that offers comprehensive solutions. This includes a combination of biomarkers, high-throughput automated systems, syndromic testing, and point-of-care diagnostics. These tools are designed to help caregivers make rapid, informed decisions about antimicrobial use, from determining whether a patient needs an antiviral or antibiotic—or neither—to selecting the optimal drug, administration route, dosage, and treatment duration. Integrating these elements is essential to ensuring that the right patient receives the right drug at the right time.

For example, in 2021, Roche Diagnostics acquired GenMark Diagnostics and its proprietary multiplex technology. This syndromic panel testing can detect multiple pathogens and antibiotic resistance elements in a single test, providing critical information that allows caregivers to deliver timely and effective solutions to patients.

Looking to the future, what opportunities in AMR or infectious diseases are most exciting to you?

Michael Lobritz: One of the biggest challenges has been the introduction of new chemical classes. A small number of these classes have historically driven the development of enough antibiotics to create the invisible infrastructure of modern medical care that we rely on. Although bringing a novel chemical class to patients might sound straightforward, it’s been over 50 years since the last one reached patients for some priority pathogens.

I’m encouraged by some of Roche’s recent innovations in discovering new chemotypes and binding motifs, which bring fresh concepts and can spark further innovation. Each breakthrough has the potential to fuel a significant amount of future work. I’m hopeful we’ll see the launch of one or more new targets and chemical classes that can act as catalysts for continued advancement in the field.

Thank you, Michael, for these insights. Final question: What is your call to action for our industry?

Michael Lobritz: AMR is often referred to as a “silent pandemic.” If we think about our recent experience with COVID-19, the impact of such an outcome couldn’t be clearer, right? What differentiates AMR from the COVID-19 pandemic is the speed and timeline. We’ve known about AMR for decades. Another difference is that COVID-19 and AMR pandemics follow different trajectories, which makes it harder for AMR to be perceived as having the urgency that it does. COVID-19 emerged rapidly and had a dramatic effect. AMR, however, is creeping forward insidiously and unevenly around the world. It’s really essential that we look with clear eyes at AMR as a scale problem that will impact everyone globally. High rates of AMR, including resistance to antibiotics used to treat common bacterial infections, have been observed worldwide. It’s a current reality—not just a future threat. This is why the WHO has declared it one of the top 10 global public health threats facing humanity. So my call to action is simple: we must see AMR for the serious threat it is and come together to address it with the urgency it demands. This is a solvable problem, but only if we recognize its scale and commit to collective action.