Here’s how it works. Proteins need to fold into very precise shapes to do their jobs, and misfolded proteins are wastes of space. Bacteria dispose of these useless molecules with ClpP—a janitorial protein that digests other proteins. It works with a partner, which recognises misfolded proteins, unfolds them, and threads them through a hole in the middle of ClpP so they can be broken down. But ADEP4 opens ClpP up so it no longer needs its partner. The janitor now becomes an assassin, running amok and chopping up any protein it comes across, misfolded or not.
The Bayer scientists showed that ADEP4 can force fast-growing cells to self-destruct, but Lewis suspected that it would do the same to persisters. Afterall, ClpP’s partner requires energy to do its job, but ClpP itself doesn’t. Once ADEP4 opens it up, it should go about its fatal business even in a dormant cell.
Lewis’ team found that ADEP4 did effectively kills persister populations of Staphylococcus aureus, but the bacteria bounce back. ClpP isn’t essential, so the bacteria just inactivated it to evolve their way around ADEP4. This, says Lewis, is why Bayer stopped working on the drug.
His solution was to pair ADEP4 with another antibiotic called rifampycin. ADEP4 would kill off the majority of the persisters, and if any of the rest started growing again, rifampycin would finish them off. He predicted that the double-whammy would leave very few survivors, maybe just a thousand cells or so.
“That’s not what we saw,” he says. “What we saw was complete sterilisation.”
This is a very nice effort. As our efforts fail to find “magic bullet” antibiotics fail and antibiotic resistance increases combo drug solutions offer some hope. While this is good news, the overall state of our ability to treat bacterial infections continues to decline as our misuse of antibiotics has greatly increased the speed at which antibiotic resistance has developed in bacteria.
This solution only works on gram positive antibiotics. ADEP4 is too big to pass through the extra outer layers of the gram-negative bacteria like ecoli and salmonella.
Related: Entirely New Antibiotic Developed, Platensimycin (2006) (2013 update: Platensimycin is a very effective antibiotic in vivo when continuously administered to cells, however this efficacy is reduced when administered by more conventional means. Efforts continue to find a way to create delivery options that are successful in treating people.) – New Family of Antibacterial Agents Discovered (2009) – Potential Antibiotic Alternative to Treat Infection (2012)