TY - JOUR

T1 - Cystobactamid 507

T2 - Concise synthesis, mode of action, and optimization toward more potent antibiotics

AU - Elgaher, Walid A.M.

AU - Hamed, Mostafa M.

AU - Baumann, Sascha

AU - Herrmann, Jennifer

AU - Siebenbürger, Lorenz

AU - Krull, Jana

AU - Cirnski, Katarina

AU - Kirschning, Andreas

AU - Brönstrup, Mark

AU - Müller, Rolf

AU - Hartmann, Rolf W.

N1 - Funding information: We thank Professor Andreas Speicher for supporting the conformational study, Dr. Josef Zapp for NMR measurements, and Dr. Volker Huch for X?ray structure determinations. W.A.M.E. gratefully acknowledges a scholarship from the German Academic Exchange Service (DAAD).

PY - 2020/1/26

Y1 - 2020/1/26

N2 - Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.

AB - Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.

KW - antibiotics

KW - conformation analysis

KW - drug design

KW - hydrogen bonds

KW - total synthesis

UR - http://www.scopus.com/inward/record.url?scp=85084218249&partnerID=8YFLogxK

U2 - 10.1002/chem.202000117

DO - 10.1002/chem.202000117

M3 - Article

C2 - 31984562

AN - SCOPUS:85084218249

VL - 26

SP - 7219

EP - 7225

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

IS - 32

ER -