Vancomycin Derivatives That Inhibit Peptidoglycan Biosynthesis Without Binding d -Ala- d -Ala

Abstract

Vancomycin is an important drug for the treatment of Gram-positive bacterial infections. Resistance to vancomycin has begun to appear, posing a serious public health threat. Vancomycin analogs containing modified carbohydrates are very active against resistant microorganisms. Results presented here show that these carbohydrate derivatives operate by a different mechanism than vancomycin; moreover, peptide binding is not required for activity. It is proposed that carbohydrate-modified vancomycin compounds are effective against resistant bacteria because they interact directly with bacterial proteins involved in the transglycosylation step of cell wall biosynthesis. These results suggest new strategies for designing glycopeptide antibiotics that overcome bacterial resistance.

Multivalent Antibiotics via Metal Complexes: Potent Divalent Vancomycins against Vancomycin-Resistant Enterococci

“…Compounds 2a-d were purified using reversed-phase HPLC according to modified literature procedure 13 and characterized by high field 1 H NMR spectroscopy and mass spectrometry (MS). The attachment of the ligands to the C-terminal of Van 4 ] 10+ , the activity of the mixture of 2d and Zn-(OAc) 2 (4:1, at pH ) 7) against VRE is the same as that of 2d, suggesting that there is no multivalent Van formed by metal complexation when 2d and Zn(OAc) 2 react at the condition of the in vitro experiment. We also did not observe the formation of [Zn(2d) n ] (2n+2)+ (n ) 1-4) by ESI-MS, which is consistent with the observed activity.…”

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by 13C{19F} and 15N{19F} Rotational-Echo Double Resonance

“…aureus cells were grown in 300 ml of defined media (20) containing [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glycine and L-[ε -15 N]lysine. The cells were harvested at OD 660 = 1.0 and were complexed with 6.7 mg (4.0 μmoles) of FPBV, resulting in 66% cell-wall binding-site occupancy (15).…”

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

“…6). The second theory holds that 2 has a second mechanism of action that is independent of peptide binding (7).…”

“…We proposed the second theory after discovering that analogues of 2 in which the peptide-binding pocket is damaged (5) still have activity against resistant microorganisms (7). These analogues were shown to inhibit the transglycosylation step of peptidoglycan biosynthesis, and we thus suggested that 2 and 5 interact directly with a component of the transglycosylation complex.…”