A biosynthetic gene cluster for the acetyl-CoA carboxylase inhibitor andrimid.
Increasing bacterial resistance to antibiotics with conventional targets has focused attention on antibiotics with unconventional targets. One promising candidate, the acetyl-CoA carboxylase (ACC) inhibitor andrimid, is a potent, broad-spectrum antibiotic with high selectivity for prokaryotic ACC. Here, we report the use of a DNA-based approach to clone the andrimid biosynthetic gene cluster from Pantoea agglomerans, yielding a cosmid that confers robust andrimid production on Escherichia coli. This gene cluster encodes a hybrid nonribosomal peptide/polyketide (NRP/PK) synthase with several unusual features, including three enzymes that form and insert beta-phenylalanine, two transglutaminase-like enzymes that likely serve as condensation catalysts, and four densely hybrid modules that form the succinimide precursor. Unlike most type I NRPSs and PKSs, the andrimid gene cluster is a dissociated system comprised of small proteins. Therefore, future efforts can exploit the genetic manipulability of E. coli to engineer the andrimid synthase with the goal of producing a diverse set of andrimid analogues for clinical evaluation.
Jin
Mi
M
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Fischbach
Michael A
MA
Clardy
Jon
J
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000577:Amides / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000378:metabolism; D015394:Molecular Structure; D005810:Multigene Family; D020636:Pantoea / Q000378:metabolism; D011090:Polyenes / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D013388:Succinimides / Q000737:chemistry / Q000378:metabolism
D000577:Amides; D000900:Anti-Bacterial Agents; D011090:Polyenes; D011758:Pyrroles; D013388:Succinimides; C487819:moiramide B; C088069:andrimid; D000103:Acetyl-CoA Carboxylase