Structure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrases

被引:22
作者
An, Weiwei [1 ]
Holly, Katrina J. [1 ]
Nocentini, Alessio [2 ]
Imhoff, Ryan D. [1 ]
Hewitt, Chad. S. [1 ]
Abutaleb, Nader S. [3 ,4 ]
Cao, Xufeng [1 ]
Seleem, Mohamed N. [2 ,4 ]
Supuran, Claudiu T. [3 ]
Flaherty, Daniel P. [1 ,5 ,6 ]
机构
[1] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN USA
[2] Univ Florence, Dept NEUROFARBA, Sect Pharmaceut & Nutraceut Sci, Florence, Italy
[3] Virginia Polytech Inst & State Univ, Virginia Maryland Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24061 USA
[4] Virginia Polytech Inst & State Univ, Ctr Emerging Zoonot & Arthropod Borne Pathogens, Blacksburg, VA 24061 USA
[5] Purdue Inst Drug Discovery, W Lafayette, IN USA
[6] Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN USA
关键词
Carbonic anhydrase inhibitors; vancomycin-resistant Enterococcus; antibiotics; drug repurposing; SULFONAMIDE INHIBITION; HELICOBACTER-PYLORI; ANION INHIBITION;
D O I
10.1080/14756366.2022.2092729
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Vancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (K (i)) against the E. faecium alpha-CA (Ef alpha-CA) and gamma-CA (Ef gamma-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and K (i) for each CA.
引用
收藏
页码:1838 / 1844
页数:7
相关论文
共 25 条
[11]   Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors [J].
Mannelli, Lorenzo Di Cesare ;
Micheli, Laura ;
Carta, Fabrizio ;
Cozzi, Andrea ;
Ghelardini, Carla ;
Supuran, Claudiu T. .
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2016, 31 (06) :894-899
[12]   Structure Activity Relationship for Sulfonamide Inhibition of Helicobacter pylori α-Carbonic Anhydrase [J].
Modak, Joyanta K. ;
Liu, Yu C. ;
Supuran, Claudiu T. ;
Roujeinikova, Anna .
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (24) :11098-11109
[13]   THE LIFE AND TIMES OF THE ENTEROCOCCUS [J].
MURRAY, BE .
CLINICAL MICROBIOLOGY REVIEWS, 1990, 3 (01) :46-65
[14]   Carbonic anhydrase inhibitors:: DNA cloning and inhibition studies of the α-carbonic anhydrase from Helicobacter pylori, a new target for developing sulfonamide and sulfamate gastric drugs [J].
Nishimori, I ;
Minakuchi, T ;
Morimoto, K ;
Sano, S ;
Onishi, S ;
Takeuchi, H ;
Vullo, D ;
Scozzafava, A ;
Supuran, CT .
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (06) :2117-2126
[15]   Anion inhibition studies of the α-carbonic anhydrases from Neisseria gonorrhoeae [J].
Nocentini, Alessio ;
Hewitt, Chad S. ;
Mastrolorenzo, Margaret D. ;
Flaherty, Daniel P. ;
Supuran, Claudiu T. .
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2021, 36 (01) :1061-1066
[16]   Anion inhibition studies of the Zn(II)-bound ι-carbonic anhydrase from the Gram-negative bacterium Burkholderia territorii [J].
Petreni, Andrea ;
De Luca, Viviana ;
Scaloni, Andrea ;
Nocentini, Alessio ;
Capasso, Clemente ;
Supuran, Claudiu T. .
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2021, 36 (01) :372-376
[17]   Transcriptional landscape and essential genes of Neisseria gonorrhoeae [J].
Remmele, Christian W. ;
Xian, Yibo ;
Albrecht, Marco ;
Faulstich, Michaela ;
Fraunholz, Martin ;
Heinrichs, Elisabeth ;
Dittrich, Marcus T. ;
Mueller, Tobias ;
Reinhardt, Richard ;
Rudel, Thomas .
NUCLEIC ACIDS RESEARCH, 2014, 42 (16) :10579-10595
[18]   The streptococci [J].
Sherman, JM .
BACTERIOLOGICAL REVIEWS, 1937, 1 (01) :3-97
[19]   Antimicrobial-Resistant Pathogens Associated with Healthcare-Associated Infections: Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010 [J].
Sievert, Dawn M. ;
Ricks, Philip ;
Edwards, Jonathan R. ;
Schneider, Amy ;
Patel, Jean ;
Srinivasan, Arjun ;
Kallen, Alex ;
Limbago, Brandi ;
Fridkin, Scott .
INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY, 2013, 34 (01) :1-14
[20]   Prokaryotic carbonic anhydrases [J].
Smith, KS ;
Ferry, JG .
FEMS MICROBIOLOGY REVIEWS, 2000, 24 (04) :335-366