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By Norman Zhou

Norman Zhou-finalAntibiotics are antimicrobial agents that have been used to treat and prevent bacterial infections for nearly a century. However, in recent decades, commonly used antibiotics are losing their efficacy against many types of bacteria. Some bacteria strains have become so resistant to the antibiotics that they are unbeatable with today’s medicines. Strains of bacteria that are resistant to almost all existing antibiotics are called “superbugs”. According to the Centers for Disease Control and Prevention (CDC), more than two million people are infected by these superbugs, and these infections directly lead to over 23,000 deaths every year in the U.S.

Clearly, it is critical that the biopharmaceutical industry move forward to develop novel antibacterial agents against superbugs, which are threatening the lives of many vulnerable patients. The first step to develop novel antibiotics is to test these drugs in animal models. However, understanding the time course of bacterial infection and the treatment effects of novel antibiotics in animal models is considerably limited by the need to use large numbers of animals and labor intensive colony forming unit (CFU) enumeration techniques to measure the bacterial burden. These inherent limitations are further exacerbated by high variability between animals and the fact that each animal can only generate data at a single time point. Thus, development of methods to enable in-life tracking of bacterial burden has the potential to mitigate some of the current hurdles associated with animal models of bacterial infection.

Scientists from Genentech have developed a novel method to monitor bacterial infection in live animals by imaging the bioluminescence, the light produced by a chemical reaction within live bacteria that infect the animals. A luminescent gene was stably expressed in a highly prevalent strain of methicillin-resistant Staphylococcus aureus (MRSA), one strain of superbug. Severe combined immunodeficiency (SCID) mice were injected intravenously with this strain of luminescent bacteria. The bacterial infection was monitored by the in vivo bioluminescent imaging method.

In this way, we were able to track in real time the kinetics of the bacterial infection with or without antibiotics treatment. The results of bioluminescent imaging correlated well with the results of the traditional CFU enumeration. The bioluminescent imaging data provided longitudinal data around the bacterial burden change in the live animal in the presence or absence of antibiotics treatment, which is critical to translate the findings from animal models to human patients. Moreover, the imaging data also facilitated the identification of clinically measurable and monitorable biomarkers that reflect the kinetics of the bacterial burden. Once validated in the clinics, these biomarkers can be extremely valuable in the assessment of antibiotic treatment effect in the patients.

The research, titled “Assess Longitudinal Pharmacodynamic Biomarker of S. aureus Infection In Vivo Using a Novel Bioluminescence Imaging Method,” will be presented at the AAPS National Biotechnology Conference in San Francisco from 10:00 am–4:30 pm on Wednesday, June 10.

Norman Zhou, Ph.D., is currently the lead PK/PD scientist for early development projects of biologics and antibody drug conjugates at Genentech. He has expertise in pharmacokinetics, pharmacodynamics, and biomarker in the infectious disease, oncology, and immunology therapeutic areas.