Details
| Original language | English |
|---|---|
| Pages (from-to) | 16641-16649 |
| Number of pages | 9 |
| Journal | Journal of the American Chemical Society |
| Volume | 140 |
| Issue number | 48 |
| Publication status | Published - 5 Dec 2018 |
| Externally published | Yes |
Abstract
To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- General Chemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Chemical Engineering(all)
- Colloid and Surface Chemistry
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In: Journal of the American Chemical Society, Vol. 140, No. 48, 05.12.2018, p. 16641-16649.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Adaptation of a Bacterial Multidrug Resistance System Revealed by the Structure and Function of AlbA
AU - Sikandar, Asfandyar
AU - Cirnski, Katarina
AU - Testolin, Giambattista
AU - Volz, Carsten
AU - Brönstrup, Mark
AU - Kalinina, Olga V.
AU - Müller, Rolf
AU - Koehnke, Jesko
N1 - Funding Information: J.K. acknowledges the DFG for an Emmy-Noether Fellowship (KO 4116/3-1). We thank Daniel Sauer for the help he provided with mass spectrometry and Prof. Lawrence Shapiro for critical reading of the manuscript. We are grateful for access to ESRF beamlines ID29 and ID23-1.
PY - 2018/12/5
Y1 - 2018/12/5
N2 - To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.
AB - To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.
UR - http://www.scopus.com/inward/record.url?scp=85058095234&partnerID=8YFLogxK
U2 - 10.1021/jacs.8b08895
DO - 10.1021/jacs.8b08895
M3 - Article
C2 - 30422653
AN - SCOPUS:85058095234
VL - 140
SP - 16641
EP - 16649
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 48
ER -