34 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Letters
(9) Finking, R.; Neumu¨ller, A.; Solsbacher, J.; Konz, D.; Kretzschmar,
G.; Schweitzer, M.; Krumm, T.; Marahiel, M. A. Aminoacyl
adenylate substrate analogues for the inhibition of adenylation
domains of nonribosomal peptide synthetases. Chembiochem 2003,
4, 903-906.
(10) May, J. M.; Finking, R.; Wiegeshoff, F.; Weber, T. T.; Bandur, N.;
Koert, U.; Marahiel, M. A. Inhibition of the D-alanine: D-alanyl
carrier protein ligase from Bacillus subtilis increases the bacterium’s
susceptibility to antibiotics that target the cell wall. FEBS J. 2005,
272, 2993-3003.
(11) May, J. J.; Kessler, N.; Marahiel, M. A.; Stubbs, M. T. Crystal
structure of DhbE, an archetype for aryl acid activating domains of
modular nonribosomal peptide synthetases. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 12120-12125.
(12) Gulick, A. M.; Lu, X.; Dunaway-Mariano, D. Crystal structure of
4-chlorobenzoate: CoA ligase/synthetase in the unliganded and aryl
substrate-bound states. Biochemistry 2004, 43, 8670-8679.
(13) Sieber, S. A.; Marahiel, M. A. Molecular mechanisms underlying
nonribosomal peptide synthesis: approaches to new antibiotics. Chem.
ReV. 2005, 105, 715-738.
(14) Kim, S.; Lee, S. W.; Choi, E.-C.; Choi, S. Y. Aminoacyl-tRNA
synthetases and their inhibitors as a novel family of antibiotics. Appl.
Microbiol. Biotechnol. 2003, 61, 278-288.
(15) Schimmel, P.; Tao, J.; Hill, J. Aminoacyl tRNA synthetases as targets
for new anti-infectives. FASEB J. 1998, 12, 1599-1609.
(16) Copeland, R. A. In EValuation of Enzyme Inhibitors in Drug
DiscoVery; Wiley: Hoboken, NJ, 2005; pp 202-203.
(17) Ferreras, J. A.; Ryu, J.-S.; Lello, F. D.; Tan, D. S.; Quadri, L. E. N.
Small-molecule inhibition of siderophore biosynthesis in Mycobac-
terium tuberculosis and Yersenia pestis. Nature Chem. Biol. 2005,
1, 29-32.
(18) Isono, K.; Uramoto, M.; Kusakabe, H.; Miyata, N.; Koyama, H.;
Ubukata, M.; Sethi, S. K.; McCloskey, J. A. Ascamycin and
dealanylascamycin, nucleoside antibiotics from Streptomyces sp.. J.
Antibiot. (Tokyo) 1984, 37, 670-672.
(19) Castro-Pichel, J.; Garcia-Lopez, M. T.; De las Heras, F. G. A facile
synthesis of ascamycin and related analogs. Tetrahedron 1987, 43,
383-389.
(20) Klicic, J. J.; Friesner, R. A.; Liu, S.-Y.; Guida, W. C. Accurate
prediction of acidity constants in aqueous solution via density
functional theory and self-consistent reaction field methods J. Phys.
Chem. A 2002, 106, 1327-1335. Acidity constants were calculated
on a truncated model compounds using the pKa module of Jaguar.
See Supporting Information for details.
lost when a triazole replaces the phosphate. In addition, the
planar geometry of the triazole was a poor fit for the binding
site, requiring out of plane bending of the ring substituents.
In conclusion, we have designed, synthesized, and evaluated
a series of bisubstrate inhibitors of the adenylate-forming
enzyme MbtA. These studies focused on the crucial linker
domain of the inhibitor scaffold and resulted in the identification
of acylsulfamide 10, which is a potent inhibitor of M. tuber-
culosis growth under iron-limiting conditions. Molecular model-
ing provided insight into the observed SAR profile, while
preliminary studies support the proposed mechanism of action.
This strategy represents a promising approach for the develop-
ment of a new class of antibiotics effective for the treatment of
TB.
Acknowledgment. This research was supported by the
Center for Drug Design in the Academic Health Center of the
University of Minnesota. We thank the Minnesota Supercom-
puting Institute VWL lab for computer time and Ms. Christine
Dreis for performing the cytotoxicty assay.
Supporting Information Available: Experimental details (1H,
13C NMR, HRMS, HPLC) for intermediates and final products,
growth inhibition assay of M. tuberculosis H37Rv under iron-
deficient conditions, dose-response curves for inhibitors 7-10,
cytotoxicity assay, molecular modeling of MbtA, siderophore
radioassay, pKa calculations and measurements. This material is
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