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 -