A research team from the Florida campus of Scripps Research Institute has identified a novel mechanism of drug resistance. The researchers say this discovery has the potential for a major impact on the development of two high potency antibiotic medicine 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, Ph.D., a TSRI professor who led the study (“Mechanisms of Self-Resistance in the Platensimycin- and Platencin-Producing Streptomyces platensis MA7327 and MA7339 Strains”). The study was published online in Chemistry & Biology.
The research focuses on Streptomyces plantensis, a bacterium that protects itself from other bacteria by secreting antibacterial substances. Streptomyces plantensis is part of a large family of antibiotic-producing bacteria. This family of bacteria accounts for more than two thirds of naturally occurring clinically useful antibiotics.
The antibiotics secreted by S. Plantensis, called platensimycin (PTM) and placencin (PTN) work by interfering with the synthesis of fatty acid, which is essential for production of cell walls.
The question remained: why did these compounds kill other bacteria but not S. plantensis? Using genetic and bioinformatic techniques, the researchers identified two complementary mechanisms in the bacteria that give resistance to platensimycin and platencin. To explain, the study discovered a pair of genes in S. plantensis that exploit a pathway to simplify fatty acid synthesis while also lessening the sensitivity to these particular antibiotics.
“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, Ph.D.
“We now identify two mechanisms for PTM and PTN resistance in the S. platensis producers—the PtmP3 or PtnP3 gene within the PTM-PTN or PTN biosynthetic cluster and the FabF gene within the fatty acid synthase locus,” wrote the investigators of this study. “PtmP3/PtnP3 and FabF confer PTM and PTN resistance by target replacement and target modification, respectively. PtmP3/PtnP3 also represents an unprecedented mechanism for fatty acid biosynthesis in which FabH and FabF are functionally replaced by a single condensing enzyme. These findings challenge the current paradigm for fatty acid biosynthesis and should be considered in future development of effective therapeutics targeting fatty acid synthase.”
Source article: http://goo.gl/SxaymW
Image: Depiction of bacteria, found on google images.