Dr. Bonomo Shares History of Lifesaving Translational Research for Treating MDR Infections

Dr. Robert Bonomo, MD, Professor of Medicine, Pharmacology, Molecular Biology and Microbiology, and Chief at the Louis Stokes Cleveland Department of Veteran Affairs, is a longstanding contributor to the American Society for Microbiology (ASM), having served in leadership literature review roles for over 13 years. He gave a vast presentation at the recent 2017 ASM Microbe conference that started with his most inspirational experiences that shaped who he has become. He then described several touching real-life stories of translational research saving lives.

To begin his presentation, Dr. Bonomo told the story of how, in 1983, he met his paternal grandfather for the first time in Italy. His grandfather put him on his knee and told him Sardinian stories about soldiers scaling walls. These soldiers would encourage each other with, “sempre avanti,” ever forwards and don’t look back!

The inspiration around him continued to encourage his development and he described several formative heroes from his childhood in the Bronx, including a Gertrude Belle Elion, PhD(h), who taught him, “Don’t be afraid of hard work. Nothing worthwhile comes easily. Don’t let others tell you that you can’t do it.” In addition, Dr. Bonomo described how he will never forget when Nobel prize winner and discoverer of the polio virus, Frederick Chapman Robbins, MD, spent an hour with his 5-year-old child at the time, explaining how polio virus was so important. Dr. Bonomo remarked that he will always appreciates his first biochemistry mentor, the inimitable Richard Hanson, PhD.

As a young practicing physician, Dr. Bonomo was amazed that a one amino acid substitution could take a 10-billion-dollar drug and render it useless. He was impressed and drawn to this research. After 4 years of private practice, he decided that he wanted to do something with research to address why lifesaving antibiotics were losing their efficacy. It was a pivotal time.

Dr. Bonomo was fascinated with the possibility of looking at a drug structure and being able to predict with some certainty how it will affect an inhibition, and then witnessing expected clinical activities. In his presentation, he described how he worked with collaborator after collaborator, some with over 100 projects together, to understand how to make more effective and potentially lifesaving β -lactamase inhibitors.

Compared to tazobactam, new inhibitors could get into the enzyme active site and stay, making them highly advantageous. But, then, the carbapenemases came. Dr. Bonomo described them as the “four horsemen,” with a precipitous trajectory to the gates of hell. These enzymes changed the game. No drug could be used! Previously, antibiotics had added 10 years to life for all of us, but now this was threatened with the carbapenemases.

Then a non-β-lactam β-lactamase inhibitor, Avibactam, showed remarkable broad-spectrum activity in being able to inhibit classes A, C, and some class D β-lactamases. There are 5 or 6 variants now in different stages of evaluation today. This became an important lifesaver for patients with multidrug-resistant (MDR) infections.

Dr. Bonomo then went on to describe boronic acid β-lactamase inhibitors, such as SO203, a drug with potent nanomolar activity against class C β-lactamases. Analysis of S0203 has revealed that energetic considerations can be as important as the biochemical. In fact, when remarking on a new study with the drug, Dr. Bonomo shared that they received exciting information late one night via, text message, that when mice in the study were challenged with Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria, only those mice treated with cefepime, together with S0203, survived. These were exciting results that made them feel like “they got new legs” in their search.

Dr. Bonomo shared another story which highlighted how a polymerase chain reaction electrospray ionization mass spectrometry (PCR/ESI-MS) molecular platform made a difference for a patient who had a brain infection, the results of which changed the patient’s life for the better. However, Dr. Bonomo stressed that how well a molecular diagnostic test works in a clinical study is still a very pressing question. In particular, how well molecular diagnostics work to make treatment decisions, depends on the prevalence of false positive data.

In perhaps the most touching story of his presentation, Dr. Bonomo recounted a case of a 19-year-old renal transplant patient with metallo-β-lactamase-producing Stenotrophomonas maltophilia, refractory to conventional treatment after many antibiotic therapies. The unfortunate patient had experienced bacteremia for more than 50 days! It was a horrible situation, and indeed, Dr. Bonomo had to stop presenting for a moment as he choked up, “your heart goes out.” Fortunately, Maria Fernanda Mojica, PharmD and her colleagues did excellent work and were able to figure out that you can bypass the ligand (L)1 inhibition problem with coadministration of CAZ-avibactam (AVI) (CZA) and aztreonam (ATM). CAZ served as the primary substrate for L1, while AVI inhibited L2 and allowed ATM to bypass inactivation. Accordingly, they successfully reached the penicillin-binding proteins of S. maltophilia, likely PBP3. They were able save this person’s life. Unfortunately, methods to identify potentially synergistic drug combinations are not readily available.

Dr. Bonomo stressed that there is no time to lose and that there are many more different compounds and rapid diagnostic that need to be examined and enacted. Highlighting the paramount clinical significance of so much biochemical and molecular research, Dr. Bonono received a standing ovation.

Feature Image Source: Rutgers New Jersey Medical School website: http://njms.rutgers.edu/research/cetr/sab_bonomo.cfm​.

W. Todd Penberthy, PhD is a medical writer with over 4 years of experience based in Orlando, Florida. Prior to that Todd was a professor directing biomedical research using zebrafish models of human disease with expertise in orthomolecular niacin-related science for 10 years.