The development of antibiotics to reduce bacterial infections in the 1940s drastically changed health care. Despite benefits from this development, a steady increase in the number of bacteria that are resistant to various antibiotics have become a major threat to public health.
Drug-resistant bacteria are problematic because they are resistant to many currently available antibacterial agents, resulting in ineffective treatments of diseases. According to the Center for Disease Control, at least 23,000 Americans die each year because of antibiotic-resistant bacteria.
“One of the problems with bacterial resistance is that the appearance of drug resistant bacteria far outpaces the development of new antibiotics,” microbiology Prof. Dr. Kodi Ravichandran said. “Moreover, some potent previously used antibiotics were discontinued over the years because they were found to be toxic to humans.
Antibiotics that are no longer in use may hold the key to dealing with this new phenomenon.
“One possible resolution is to resurrect older antibiotics by tinkering with the toxic parts of the molecule so that it does not affect mammalian tissue, but leaving the antibacterial parts of the drug so that it can still be bactericidal,” Ravichandran said.
In their most recent study, Ravichandran and Pharmacology department chair Dr. Douglas A. Bayliss studied the interactions of trovafloxacin, an outdated toxic antibiotic, and found it inhibited specialized channels along a cell’s plasma membrane, known as mammalian pannexin channels, causing apoptosis, the process of cell death, to accelerate. This causes cells to fragment irregularly.
Apoptosis occurs around 200 billion times each day and is a balancing act indispensable to normal cell turnover and the development of the body systems. The proper execution of cell death process is influenced by pannexin channels, which span the cell’s plasma membrane.
Pannexin 1 channels, which are expressed by many cell types in the body, specifically regulate the influx and efflux of molecules throughout cell differentiation, activation and cell death.
During cell death, the dying cell begins the process of cellular disassembly, which includes formation of membrane blebs. When pannexin channels are not performing properly, the dying cells fall apart quickly.
Ravichandran’s study found that the antibiotic trovafloxacin, by inhibiting PANX1 channels, affects how quickly the apoptotic cells fall apart, and causing irregular fragmentation of cells during which the cells release an excess of apoptotic vesicles.
Because of the cross-reaction between trovafloxacin and the mammalian pannexin channels, Ravichandran hopes to “find out which parts of the antibiotic affect mammalian components, and potentially tinker with them so that they can’t target pannexin channels, but can inhibit bacterial growth” in an effort to develop drugs that will limit the toxicity to human cells but keep their antibacterial property.
