Drug resistance mechanism could impact development of two antibiotic drug candidates

Now, a new study by scientists from the Florida campus of The Scripps Research Institute (TSRI) has uncovered a mechanism of drug resistance. This knowledge could have a major impact on the development of a pair of highly potent new antibiotic drug candidates.

"Now, because we know the resistance mechanism, we can design elements to minimize the emergence of resistance as these promising new drug candidates are developed," said Ben Shen, a TSRI professor who led the study, which was published February 20, 2014 online ahead of print by the Cell Press journal Chemistry & Biology.

Bacteria Versus Bacteria

The study centers around a kind of bacteria known as Streptomyces platensis, which protects itself from other bacteria by secreting anti-bacterial substances. Interestingly, Streptomyces platensis belongs to a large family of antibiotic-producing bacteria that accounts for more than two-thirds of naturally occurring clinically useful antibiotics.

The antibiotic compounds secreted by Streptomyces platensis, which are called platensimycin and platencin and were discovered only recently, work by interfering with fatty acid synthesis. Fatty acid synthesis is essential for the production of bacterial cell walls and, consequently, the bacteria's existence. Platencin, although structurally similar to platensimycin, inhibits two separate enzymes in fatty acid synthesis instead of one.

The question remained, though, of why these compounds killed other bacteria, but not the producing bacteria Streptomyces platensis.

The Path to Resistance

The scientists set out to solve the mystery.

"Knowing how these bacteria protect themselves, what the mechanisms of self-resistance of the bacteria are, is important because they could transfer that resistance to other bacteria," said Tingting Huang, a research associate in the Shen laboratory who was first author of the study with Ryan M. Peterson of the University of Wisconsin, Madison.

Using genetic and bioinformatic techniques, the team identified two complementary mechanisms in the bacteria that confer resistance to platensimycin and platencin. In essence, the study found a pair of genes in Streptomyces platensis exploits a pathway to radically simplify fatty acid biosynthesis while bestowing an insensitivity to these particular antibiotics.

"Understanding how these elements work is a big leap forward," added Jeffrey D. Rudolf, a research associate in the Shen lab who worked on the study. "Now these bacteria have shown us how other bacteria might use this resistance mechanism to bypass fatty acid biosynthesis inhibition."