Antibiotic Discovery and Mechanisms of Action

        Antibiotic resistance among bacteria is a steadily growing problem. Once easily treated with penicillin, infections caused by methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE) are now very difficult to combat. Cases of extremely drug resistant gram negative bacteria are becoming increasingly common in and threaten to spread throughout the world.  Without effective antibiotics for these extremely drug resistant organisms, even countries with well-developed health care systems will have few treatment options. Therefore, the need for new antibiotics that are active against multidrug resistant pathogens is more urgent than ever before. Unfortunately, the number of new antibiotics being brought to market is currently insufficient to keep pace with the rate of antibiotic resistance development.

We are focused on three related areas of antibiotic research. First, we are studying some of the latest antibiotics to enter the clinic as well as preclinical molecules to determine their mechanisms of action. Second, we are trying to understand how resistance arises to these new antibiotics and how treatment can be modified to lead to a more successful clinical outcome. Third, we have developed a new method for screening for novel antibiotics and determining their mechanisms of action. We are using this method to screen libraries of natural products for novel compounds active against multidrug resistant bacteria. To accomplish these goals, we have set up collaborations with clinicians at the UCSD School of Medicine, with pharmaceutical companies who have promising new antibiotics, and with chemists who can provide novel compounds for screening for new antibiotics.

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A refined model for the mechanism of action of daptomycin.  Upon insertion into the membrane daptomycin (light blue “cups” with yellow circles) causes distortions that misdirect the localization of key cell wall proteins such as DivIVA, leading to bent cells below the MIC (left) and lethality above the MIC (right).   Shown are phosphatidylglycerol (green lipids), cardiolipin (yellow lipids), potassium ions (green circles), and DivIVA (blue ovals).


(Pogliano, J, Pogliano, N, Silverman, JA. 2012. Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins. J. Bacteriol. 194:4494-4504. doi: 10.1128/JB.00011-12; 10.1128/JB.00011-12.)