HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis

Abstract

We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg2+/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the x-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg2+ binding hypothesis, together with the x-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound 45 had cell growth inhibition MIC90 values of ~250–500 ng/mL against S. aureus, 500 ng/mL against Bacillus anthracis, 4 μg/mL against Listeria monocytogenes and Enterococcus faecium, and 1 μg/mL against Streptococcus pyogenes M1, but very little activity against E. coli (DH5α, K12) or human cell lines.

Antibacterial drug leads targeting isoprenoid biosynthesis

“…5 A and B, both diketoacids bind to site 4, with 14 also binding to site 3. The observation that 15 binds only to site 4 is of interest because this inhibitor has very good antibiotic activity (10). Plus, the occupation of site 4 in both structures is consistent with the results for the other potent anionic inhibitors (Fig.…”

“…1). Formation of 4 is catalyzed by the enzyme undecaprenyl diphosphate synthase (UPPS), and several UPPS inhibitors have been reported (3)(4)(5)(6)(7)(8)(9)(10). UPP is then hydrolyzed to the monophosphate, which is next converted to lipid I and lipid II, leading to formation of cell wall peptidoglycan ( Fig.…”

“…Based on in silico high-throughput screening (9) and hit development (Fig. S1), we produced a small series of benzoic (9)(10)(11)(12), phosphonic (13), and diketoacids (14, 15) that had activity against UPPS (Fig. 2).…”

“…We next determined the structures of the three potent benzoic acid inhibitors (10)(11)(12) (Fig. 2) bound to UPPS (Fig.…”

Physiologic Activity of Bisphosphonates – Recent Advances

“…The finding that keto-and diketo-acids bind to the Mg(II)/Asp domain of HIV integrase in a manner similar to that observed upon their binding with prenyl transferases stimulated interest in possible use of bisphosphonates as its inhibitors [178]. This resulted in the synthesis and evaluation of several inhibitors of this enzyme (Scheme 10) [190 -192].…”