Total Syntheses and Initial Evaluation of [Ψ[C(═S)NH]Tpg⁴]vancomycin, [Ψ[C(═NH)NH]Tpg⁴]vancomycin, [Ψ[CH₂NH]Tpg⁴]vancomycin, and Their (4-Chlorobiphenyl)methyl Derivatives: Synergistic Binding Pocket and Peripheral Modifications for the Glycopeptide Antibiotics

Abstract

Full details of studies are disclosed on the total synthesis of binding pocket analogues of vancomycin, bearing the peripheral L-vancosaminyl-1,2-D-glucosyl disaccharide, that contain changes to a key single atom in the residue 4 amide (residue 4 carbonyl O → S, NH, H2) designed to directly address the underlying molecular basis of resistance to vancomycin. Also disclosed are studies piloting the late stage transformations conducted on the synthetically more accessible C-terminus hydroxymethyl aglycon derivatives and full details of the peripheral chlorobiphenyl functionalization of all the binding pocket modified vancomycin analogues designed for dual D-Ala-D-Ala/D-Ala-D-Lac binding are reported. Their collective assessment indicate that combined binding pocket and chlorobiphenyl peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, VanA and VanB VRE) and impressive potencies against both vancomycin-sensitive and vancomycin-resistant bacteria (MICs = 0.06–0.005 μg/mL and 0.5–0.06 μg/mL for the amidine and methylene analogues, respectively) and likely benefit from two independent and synergistic mechanisms of action, only one of which is dependent on D-Ala-D-Ala/D-Ala-D-Lac binding. Such analogues are likely to display especially durable antibiotic activity not prone to rapidly acquired clinical resistance.

Targeting Antibiotic Resistance

“…This figure can be divided into two factors: a 10‐fold decrease as a result of the loss of a hydrogen bond, and a 100‐fold decrease owing to repulsion of the lone pairs on the two nearby oxygen atoms 132. In order to try and regain the lost binding affinity, a series of vancomycin analogues was synthesized with modifications at the carbonyl group of residue 4 (Figure 27 A) 131, 133…”

“…In the case of binding to d ‐Ala‐ d ‐Ala strands, the nitrogen atom can take the role of a hydrogen‐bond acceptor, whereas in the case of binding to d ‐Ala‐ d ‐Lac strands, it can serve as a hydrogen‐bond donor. This, in combination with the introduction of a lipophilic 4‐(4‐chlorophenyl)benzyl side chain derived from oritavancin134 (which allows the antibiotic to anchor into the bacterial cell membrane, thus bringing target and host closer together), resulted in impressive antibiotic activities against both vancomycin‐sensitive and vancomycin‐resistant bacteria (MIC=0.06–0.005 and 0.5–0.06 μg mL −1 for the amidine and methylene analogues, respectively) 133…”

Developments in Glycopeptide Antibiotics

“…112,113 While 15a had similar activity to the aglycon, the additional substituent of 15b improved potency by over 100-fold against VRE, with MIC of 0.005 μg/mL for VanA E. faecalis or E. faecium and 0.06 μg/mL for VanB E. faecalis . Excellent potency was also observed against MRSA (0.03–0.06 μg/mL for 15b ; not determined for 15a ).…”

The race for antimicrobials in the multidrug resistance era

“…The conversion of D ‐Ala‐ D ‐Ala to D ‐Ala‐ D ‐Lac in the peptidoglycan termini is one of the mutations that provide resistance to native vancomycin, however, chemical modifications directed to key single‐atom sites in the binding pocket of vancomycin seem to enable the antibiotic to bind both the modified and the unaltered targets in the peptidoglycan (Crowley and Boger, 2006; Xie et al ., 2012; Okano et al ., 2015). Peripheral structural modifications, such as a (4‐chlorobiphenyl) methyl (CBP) group, increased the antimicrobial potency of vancomycin and provided, with multiple synergistic mechanisms of action, a delay in the emergence of resistance (Okano et al ., 2014, 2015).…”

“…Peripheral structural modifications, such as a (4‐chlorobiphenyl) methyl (CBP) group, increased the antimicrobial potency of vancomycin and provided, with multiple synergistic mechanisms of action, a delay in the emergence of resistance (Okano et al ., 2014, 2015). This chemical modification served as a starting point for the introduction of further single peripheral modifications at the C‐terminus, which led to a battery of new and improved versions of vancomycin against a vancomycin‐resistant pathogen (VanA VRE).…”