Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

Abstract

The rapid rise of multi-drug-resistant bacteria is a global healthcare crisis, and new antibiotics are urgently required, especially those with modes of action that have low-resistance potential. One promising lead is the liposaccharide antibiotic moenomycin that inhibits bacterial glycosyltransferases, which are essential for peptidoglycan polymerization, while displaying a low rate of resistance. Unfortunately, the lipophilicity of moenomycin leads to unfavourable pharmacokinetic properties that render it unsuitable for systemic administration. In this study, we show that using moenomycin and other glycosyltransferase inhibitors as templates, we were able to synthesize compound libraries based on novel pyranose scaffold chemistry, with moenomycin-like activity, but with improved drug-like properties. The novel compounds exhibit in vitro inhibition comparable to moenomycin, with low toxicity and good efficacy in several in vivo models of infection. This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction.

Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5

“…This occupancy of both S1 and S2 sites is of interest since as can be seen in Figure 3A, the alkyl side-chains have close contacts—as low as ~4 Å—as would be required for reaction of S1 and S2 site substrates. What is even more interesting is the observation that the longer n-alkyl side-chains of the ligands ( 9 , 10 ) that bind in S2 are bent at their C-terminus, as proposed [4a] for 5 during catalysis and as illustrated in Scheme 1C. The bend is induced by a wall consisting of F149, L150 and I181, Figure S8.…”

“…Moenomycin A (MmA 1 , Scheme 1) is one member of this class and in vitro is a more potent antibiotic than is vancomycin. It has, however, poor pharmacokinetics, but given the global increase in antibiotic resistance [3] there is renewed interest in the development of MmA analogs [4] , as well as the possibility of using MmA to treat gastro-intestinal tract infections, such as that caused by Helicobacter pylori [5] . MmA biosynthesis is quite complex, with 17 enzymes involved [4a] .…”

“…It has, however, poor pharmacokinetics, but given the global increase in antibiotic resistance [3] there is renewed interest in the development of MmA analogs [4] , as well as the possibility of using MmA to treat gastro-intestinal tract infections, such as that caused by Helicobacter pylori [5] . MmA biosynthesis is quite complex, with 17 enzymes involved [4a] . The first committed step involves condensation of 3-phosphoglycerate ( 2 ) with farnesyl diphosphate ( 3 ) to form 2-( Z,E) -farnesyl-3-phosphoglycerate [FPG, 4 ] in a reaction catalyzed by MoeO5 [6] and in recent work we reported the X-ray structure of MoeO5 and proposed a mechanism of action [6b] .…”

“…The first committed step involves condensation of 3-phosphoglycerate ( 2 ) with farnesyl diphosphate ( 3 ) to form 2-( Z,E) -farnesyl-3-phosphoglycerate [FPG, 4 ] in a reaction catalyzed by MoeO5 [6] and in recent work we reported the X-ray structure of MoeO5 and proposed a mechanism of action [6b] . 4 then undergoes a series of glycosylations and other modifications to form a phosphoglycolipid, the FPG-trisaccharide 5 which then reacts with geranyl diphosphate (GPP, 6 ) to produce the (C 25 ) moenocinyl trisaccharide 7 [7] which after further transformations [4a] results in formation of 1 . The 5 → 7 reaction is catalyzed by MoeN5 [4a] and has been proposed [4a] to involve two carbocations.…”

“…4 then undergoes a series of glycosylations and other modifications to form a phosphoglycolipid, the FPG-trisaccharide 5 which then reacts with geranyl diphosphate (GPP, 6 ) to produce the (C 25 ) moenocinyl trisaccharide 7 [7] which after further transformations [4a] results in formation of 1 . The 5 → 7 reaction is catalyzed by MoeN5 [4a] and has been proposed [4a] to involve two carbocations. However, the structure of MoeN5 has not been reported and a BLAST (Basic Local Alignment Search Tool) search reveals no homologs with known structure.…”