UVA Medical Researchers Develop New Antibiotic

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University of Virginia medical researchers announced they have a new drug that could prove to be a breakthrough for thousands of people who have Crohn's disease. Crohn's disease is a gastro-intestinal condition, like colitis or irritable bowel syndrome (IBS).

The new drug is called Amixicile and even though it is still in clinical animal trials, researchers and doctors at UVA say its ability to fight infections in the gut could forever change the way antibiotics are developed.

Doctor Paul Hoffman has studied infectious disease his entire career. He and his medical team at UVA may have a viable cure for Clostridium difficile, an infectious intestinal disease that has one of the highest death tolls in hospitals.

"It’s the number one cause of hospital-acquired infection worldwide,” said Hoffman.

Even though Amixicile hasn't been tested on humans yet, scientists say its effects are like nothing they've ever seen.

"Even though it could kill all of the bacteria in the intestine, it only gets the ones that are causing the foul or harming your system and it protects the good guys that are not causing trouble,” said Hoffman.

The drug targets areas in the colon and intestines that are inflamed or irritated by infections. The C. difficile infection normally mutates and resists regular antibiotics. Researchers say Amixicile solves that problem and has zero negative side effects.

"All of the metrics from this showed that it’s probably as safe as drinking water. That there are no toxicities, there's no chemical modifications. The drug just is what it is,” said Hoffman.

Hoffman is excited the drug could potentially cure a wide range of diseases if the Federal Drug Administration approves it for human trials.

"We're very encouraged that we can treat so many different indications with a single medicine,” said Hoffman.

For someone who spent his life researching cures, this discovery would be a career high.

Researchers say more pre-clinical work needs to be done on mice in order to gain FDA approval, but they say the evidence they have so far is very promising.

University of Virginia Health System Press Release

CHARLOTTESVILLE, Va., July 24, 2014 – A new antibiotic being developed at the University of Virginia School of Medicine to combat the dangerous C. difficile superbug also appears effective against a wide array of other pathogens, including the Helicobacter pylori bacterium, a new study suggests. With antibiotic resistance a growing concern – and an alarming shortage of new antibiotics in development – the drug is notable because it works in a way that prevents microbes from becoming resistant to it.

UVA’s new findings challenge conventional wisdom that the best way to develop new treatments for Clostridium difficile, a growing problem in healthcare settings nationwide, is to target that infection specifically and to use an antibiotic that concentrates in the gut. UVA’s drug, Amixicile, does neither – yet early testing suggests it could be significantly more effective than existing options.

Sparing Good Gut Bacteria

Amixicile may prove particularly effective against C. difficile because, unlike other antibiotics, it spares beneficial probiotic and other beneficial bacteria. There is growing evidence to suggest that probiotic bacteria help prevent C. difficile re-infection and relapse, so antibiotics that concentrate in the gut and kill off the intestinal flora indiscriminately make it easier for C. difficile to regain a toehold. Mice infected with C. difficile that were treated with other antibiotics commonly relapsed and died, but there were no relapses in mice treated with Amixicile, the researchers report.

Unlike other C. difficile therapeutics, Amixicile concentrates in the bloodstream, rather than in the gut, and emerges only at infected sites. Thus, Amixicile may be useful in treatment of systemic anaerobic and parasitic infections as well as gastric infections caused by H. pylori. More broadly, because of its low toxicity and immunity to mutation based drug resistance; it potentially could be used as a lifelong prophylactic to prevent flare-ups of chronic diseases such as Crohn’s disease and ulcerative colitis. It may even prove effective against anaerobes associated with periodontal disease.

“If the drug works even half as well as what we’ve found to date, there would be nothing like it in the existing antimicrobials,” said Paul S. Hoffman, PhD, of the UVA Division of Infectious Diseases and International Health and the UVA Department of Microbiology, Immunology and Cancer Biology.

Overcoming Drug Resistance

Amixicile avoids the problem of mutation-based drug resistance by its unusual mechanism of action. Amixicile targets the function of the vitamin B1 cofactor of pyruvate, ferredoxin oxidoreductase, an enzyme uniquely found in anaerobic pathogens and not present in humans or in the probiotic beneficial gut bacteria.

The vitamin cofactor, a small molecule, is not susceptible to mutation, offering a remarkably reliable – and therefore very attractive – target. Because the target won’t change, the risk of bacteria becoming resistant to the antibiotic is lessened dramatically.

Next Steps

More preclinical work needs to be done before the researchers can gain FDA approval to begin testing Amixicile in people. They next intend to evaluate maximum tolerable doses in animals and examine whether the drug has any genetic or mutagenic effects. If all goes well, they will eventually proceed to human testing.

The researchers’ latest findings have been published online by Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology, and will appear in the August issue. The article was authored by Hoffman; Alexandra M. Bruce of UVA’s Department of Chemistry; Igor Olekhnovich, Cirle A. Warren and Stacey L. Burgess of UVA’s Division of Infectious Diseases and International Health; Raquel Hontecillas, Monica Viladomiu and Josep Bassaganya-Riera of the Virginia Bioinformatics Institute at Virginia Tech; Richard L. Guerrant of UVA’s Division of Infectious Diseases; and Timothy L. Macdonald of UVA’s Department of Chemistry.

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