Details
| Original language | English |
|---|---|
| Pages (from-to) | 988-997 |
| Number of pages | 10 |
| Journal | ACS infectious diseases |
| Volume | 4 |
| Issue number | 6 |
| Early online date | 27 Feb 2018 |
| Publication status | Published - 8 Jun 2018 |
| Externally published | Yes |
Abstract
The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).
Keywords
- antibiotic resistance, antivirulence agent, binding mode, elastase, Galleria mellonella, LasB, selectivity
ASJC Scopus subject areas
- Medicine(all)
- Infectious Diseases
Sustainable Development Goals
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In: ACS infectious diseases, Vol. 4, No. 6, 08.06.2018, p. 988-997.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa
AU - Kany, Andreas M.
AU - Sikandar, Asfandyar
AU - Haupenthal, Jörg
AU - Yahiaoui, Samir
AU - Maurer, Christine K.
AU - Proschak, Ewgenij
AU - Köhnke, Jesko
AU - Hartmann, Rolf W.
N1 - Funding Information: We thank Jeannine Jung, Simone Amann, Tabea Schramm, and Lilia Weizel for technical support, Dr. Jens Eberhard and Dr. Giuseppe Allegretta for help with the establishment of the LC-MS assay, Dr. Teresa Röhrig for support with the G. mellonella assay, and Dr. Martin Empting for help with molecular modeling. E.P. thanks German Research Foundation (DFG, Heisenberg-Professur PR1405/4-1) for financial support.
PY - 2018/6/8
Y1 - 2018/6/8
N2 - The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).
AB - The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).
KW - antibiotic resistance
KW - antivirulence agent
KW - binding mode
KW - elastase
KW - Galleria mellonella
KW - LasB
KW - selectivity
UR - http://www.scopus.com/inward/record.url?scp=85048292535&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.8b00010
DO - 10.1021/acsinfecdis.8b00010
M3 - Article
C2 - 29485268
AN - SCOPUS:85048292535
VL - 4
SP - 988
EP - 997
JO - ACS infectious diseases
JF - ACS infectious diseases
SN - 2373-8227
IS - 6
ER -