Pseudomonas aeruginosa bacteria (National Institute of Environmental Health Sciences, NIH)
26 January 2018. A class of antibiotics first discovered in the 1970s, but passed by as new drugs came on the market, are getting a second look as the need intensifies for better weapons to treat infections resistant to most antibiotics. An international team led by researchers at University of Queensland in Melbourne, Australia describe their work synthesizing the old drugs to treat today’s resistant infections, in yesterday’s issue of the journal Cell Chemical Biology (paid subscription required).
The researchers led by Queensland biochemistry professor Matthew Cooper are seeking new and better tools to address the growing public health crisis of infections becoming resistant to current antibiotics. Worldwide, says Cooper’s lab, bacterial infections kill some 700,000 people, including 9,000 in Australia. Centers for Disease Control and Prevention says each year some 2 million people in the U.S. alone develop infections resistant to antibiotics, resulting in at least 23,000 deaths.
Gram-negative bacteria are resistant to multiple drugs and are increasingly resistant to most available antibiotics, notes CDC. “Gram-negative bacteria,” says Cooper in a university statement, “are harder to kill as disease organisms, because they have an extra membrane to penetrate that is often hidden by a capsule or slime layer which acts to camouflage them from drugs and our immune system.”
Among the antibiotics losing their effectiveness is colistin, a drug considered for many as the last line of defense against gram-negative bacterial infections. But colistin is associated with toxicity to the kidneys, which limits its use in many patients, as well as a growing resistance to the drug.
Cooper and colleagues are revisiting a class of antibiotics called octapeptins, first developed in the 1970s. Octapeptins have a similar chemistry to colistin, consisting of lipopeptides, short amino acid chains connected to lipids, that disrupt the cell membranes of bacteria. As new so-called wonder drugs came on the market to treat infections during that period, however, octapeptins were largely ignored.
In their tests, the researchers found one type of octapeptin, called C4, active against the membranes of multi-drug resistant bacteria in lab cultures. But in tests with lab animals, octapeptin C4 was much less effective, which the researchers attribute to interference from blood plasma proteins. The team then redesigned octapeptin C4 using nuclear magnetic resonance spectroscopy, an imaging technique to investigate its chemical structure, and computational modeling to design a synthetic form of octapeptin C4.
Tests in lab cultures and mice show the redesigned drug binds much less to blood plasma proteins than the original octapeptin C4, while remaining active against multi-drug resistant bacteria. Tests with mice show the synthetic octapeptin C4 effective against Pseudomonas aeruginosa bacteria resistant to colistin. “In addition,” adds Cooper, “octapeptin was shown to be potentially less toxic to the kidneys than colistin.”
In addition to his research, Cooper is a serial entrepreneur who started 3 companies in the U.K. and Ireland. His latest company is Inflazome Ltd. in Dublin, developing therapies for inflammatory diseases.
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