Platensimycin activity against mycobacterial beta-ketoacyl-ACP synthases.
BACKGROUND
There is an urgent need for the discovery and development of new drugs against Mycobacterium tuberculosis, the causative agent of tuberculosis, especially due to the recent emergence of multi-drug and extensively-drug resistant strains. Herein, we have examined the susceptibility of mycobacteria to the natural product platensimycin.


RESULTS
We have demonstrated that platensimycin has bacteriostatic activity against the fast growing Mycobacterium smegmatis (MIC = 14 microg/ml) and against Mycobacterium tuberculosis (MIC = 12 microg/ml). Growth in the presence of paltensimycin specifically inhibited the biosynthesis of mycolic acids suggesting that the antibiotic targeted the components of the mycolate biosynthesis complex. Given the inhibitory activity of platensimycin against beta-ketoacyl-ACP synthases from Staphylococcus aureus, M. tuberculosis KasA, KasB or FabH were overexpressed in M. smegmatis to establish whether these mycobacterial KAS enzymes were targets of platensimycin. In M. smegmatis overexpression of kasA or kasB increased the MIC of the strains from 14 microg/ml, to 30 and 124 microg/ml respectively. However, overexpression of fabH on did not affect the MIC. Additionally, consistent with the overexpression data, in vitro assays using purified proteins demonstrated that platensimycin inhibited Mt-KasA and Mt-KasB, but not Mt-FabH.


CONCLUSIONS
Our results have shown that platensimycin is active against mycobacterial KasA and KasB and is thus an exciting lead compound against M. tuberculosis and the development of new synthetic analogues.
Brown
Alistair K
AK
School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Taylor
Rebecca C
RC
Bhatt
Apoorva
A
Fütterer
Klaus
K
Besra
Gurdyal S
GS
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors*; D000218:Adamantane / Q000494:pharmacology*; D062365:Aminobenzoates / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D020102:Mycobacterium smegmatis / Q000201:enzymology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009171:Mycolic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism
D062365:Aminobenzoates; D000813:Anilides; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007527:Isoenzymes; D009171:Mycolic Acids; C078182:beta-ketoacyl-acyl carrier protein synthase I; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D000218:Adamantane; C510909:platensimycin