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.
Full details of studies are disclosed on the total syntheses 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 of the binding-pocket-modified vancomycin analogues designed for dual D-Ala-D-Ala/D-Ala-D-Lac binding. Their collective assessment indicates that combined binding pocket and chlorobiphenyl peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, and VanA and VanB VRE) and impressive potencies against both vancomycin-sensitive and vancomycin-resistant bacteria (MICs = 0.06-0.005 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 that is not prone to rapidly acquired clinical resistance.
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Akinori
A
Okano
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Atsushi
A
Nakayama
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Kejia
K
Wu
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Erick A
EA
Lindsey
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Alex W
AW
Schammel
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Yiqing
Y
Feng
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Karen C
KC
Collins
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Dale L
DL
Boger
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001713:Biphenyl Compounds; D014640:Vancomycin; C006983:4-chlorobiphenyl