Details
| Original language | English |
|---|---|
| Pages (from-to) | 7219-7225 |
| Number of pages | 7 |
| Journal | Chemistry - A European Journal |
| Volume | 26 |
| Issue number | 32 |
| Publication status | Published - 26 Jan 2020 |
Abstract
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.
Keywords
- antibiotics, conformation analysis, drug design, hydrogen bonds, total synthesis
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Organic Chemistry
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Chemistry - A European Journal, Vol. 26, No. 32, 26.01.2020, p. 7219-7225.
Research output: Contribution to journal › Article › Research › peer review
}
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 -