Anion inhibition studies of the α-carbonic anhydrases from Neisseria gonorrhoeae.

Published on May 24, 2021in Journal of Enzyme Inhibition and Medicinal Chemistry4.673
· DOI :10.1080/14756366.2021.1929202
Alessio Nocentini26
Estimated H-index: 26
(UniFI: University of Florence),
Chad S. Hewitt1
Estimated H-index: 1
(Purdue University)
+ 2 AuthorsClaudiu T. Supuran152
Estimated H-index: 152
(UniFI: University of Florence)
The bacterial pathogen Neisseria gonorrhoeae encodes for an α-class carbonic anhydrase (CA, EC, NgCA, which was investigated for its inhibition with a series of inorganic and organic anions. Perchlorate and hexafluorophosphate did not significantly inhibit NgCA CO2 hydrase activity, whereas the halides, azide, bicarbonate, carbonate, stannate, perosmate, diphosphate, divanadate, perruthenate, and trifluoromethanesulfonate showed inhibition constants in the range of 1.3-9.6 mM. Anions/small molecules such as cyanate, thiocyanate, nitrite, nitrate, bisulphite, sulphate, hydrogensulfide, phenylboronic acid, phenylarsonic acid, selenate, tellurate, tetraborate, perrhenate, peroxydisulfate, selenocyanate, iminodisulfonate, and fluorosulfonate showed KIs in the range of 0.15-1.0 mM. The most effective inhibitors detected in this study were sulfamide, sulfamate, trithiocarbonate and N,N-diethyldithiocarbamate, which had KIs in the range of 5.1-88 µM. These last compounds incorporating the CS2- zinc-binding group may be used as leads for developing even more effective NgCA inhibitors in addition to the aromatic/heterocyclic sulphonamides, as this enzyme was recently validated as an antibacterial drug target for obtaining novel antigonococcal agents.
#1Koji Yahara (NIH: National Institutes of Health)H-Index: 16
#2Kevin C. Ma (Harvard University)H-Index: 7
Last. Makoto Ohnishi (NIH: National Institutes of Health)H-Index: 57
view all 18 authors...
BACKGROUND Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; however, the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown. METHODS We studied the evolution of penA alleles by obt...
5 CitationsSource
#1Nader S. Abutaleb (Purdue University)H-Index: 11
#2Ahmed E. M. Elhassanny (VT: Virginia Tech)H-Index: 4
Last. Mohamed N. Seleem (Purdue University)H-Index: 30
view all 4 authors...
Vancomycin-resistant enterococci (VRE) are a serious public health threat and a leading cause of healthcare-associated infections. Bacterial resistance to antibiotics recommended for the treatment of enterococcal infections complicates the management of these infections. Hence, there is a critical need for the discovery of new anti-VRE agents. We previously reported carbonic anhydrase inhibitors (CAIs) as new potent VRE inhibitors. In the present study, the activity of the CAI, dorzolamide was e...
2 CitationsSource
#1Chad S. Hewitt (Purdue University)H-Index: 1
#2Nader S. Abutaleb (VT: Virginia Tech)H-Index: 1
Last. Daniel P. Flaherty (Purdue University)H-Index: 10
view all 18 authors...
Neisseria gonorrhoeae is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat N. gonorrhoeae infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities. Our team has repurposed the FDA-approved carbonic anhydrase inhibitor scaffold of acetazolamide to target N. gonorrhoeae and the bacteria's essential carboni...
5 CitationsSource
#1Susanne Jacobsson (Örebro University)H-Index: 22
#2Michelle J Cole (PHE: Public Health England)H-Index: 29
Last. Magnus Unemo (Örebro University)H-Index: 73
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BACKGROUND The emergence and spread of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, nationally and internationally, is a serious threat to the management and control of gonorrhoea. Limited and conflicting data regarding the epidemiological drivers of gonococcal AMR internationally have been published. We examined the antimicrobial susceptibility/resistance of gonococcal isolates (n = 15,803) collected across 27 European Union/European Economic Area (EU/EEA) countries in 2009-2016, in...
1 CitationsSource
#1Daniel Golparian (Örebro University)H-Index: 31
Last. Magnus Unemo (Örebro University)H-Index: 73
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OBJECTIVES Surveillance of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, supported by molecular typing, ideally through genome sequencing, is imperative. We defined N. gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR) clonal complexes (CCs) and validated their usefulness in gonococcal AMR surveillance. METHODS All NG-STAR alleles and STs available in the public database ( were analysed using PHYLOViZ 2.0 to define CCs according to the closest...
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#1Alessio Nocentini (UniFI: University of Florence)H-Index: 26
#2Andrea Angeli (UniFI: University of Florence)H-Index: 23
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC generally by coordinating to the active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected by another group. We review the anion CA inhibitors (CAIs) in the more general context of drug design studies and the discovery of a large number of inhibitor classes and inhibition mechanisms, including zinc binders (sulphonamides and isosteres, dithio...
18 CitationsSource
#1Jonathan M. Turner (MUSC: Medical University of South Carolina)H-Index: 1
#2Kristie L. Connolly (USU: Uniformed Services University of the Health Sciences)H-Index: 7
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The increasing prevalence of Neisseria gonorrhoeae strains exhibiting decreased susceptibility to extended-spectrum cephalosporins (ESCs) presents a challenge for the successful treatment of gonorrhea infections. To address this challenge, we evaluated a panel of 23 cephalosporins against penicillin-binding protein 2 (PBP2) from the ESC-resistant (ESCR) N. gonorrhoeae strain H041 to determine which molecular features are important for antimicrobial activity. Structure-activity relationships (SAR...
2 CitationsSource
#1Alessandro Bonardi (UniFI: University of Florence)H-Index: 10
#2Alessio Nocentini (UniFI: University of Florence)H-Index: 26
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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The binding mode of aromatic sulphonamides and clinically licenced drugs to the three carbonic anhydrase (CA, EC isoforms from the human pathogen V. cholerae was here thouroghly characterised by a joint docking and molecular dynamics in silico protocol. In fact, VchCA, VchCAβ, and VchCAγ are crucial in the pathogen life cycle and growth and represent innovative targets to fight V. cholerae proliferation overcoming the spreading chemoresistance to the available drugs. A set of 40 sulphon...
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#1Andrea Petreni (UniFI: University of Florence)H-Index: 3
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8 CitationsSource
#1Ellen L. Aho (Concordia College)H-Index: 9
#2Jenie Ogle (Concordia College)H-Index: 2
Last. Anna Finck (Concordia College)H-Index: 2
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Neisseria gonorrhoeae infections are a serious global health problem. This organism has developed disturbing levels of antibiotic resistance, resulting in the need for new approaches to prevent and treat gonorrhea. The genus Neisseria also includes several members of the human microbiome that live in close association with an array of microbial partners in a variety of niches. We designed an undergraduate antibiotic discovery project to examine a panel of nonpathogenic Neisseria species for thei...
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Cited By1
#1Linda J. Urbański (UTA: University of Tampere)H-Index: 2
#2Daniela Vullo (UniFI: University of Florence)H-Index: 69
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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Pathogenic bacteria resistant to most antibiotics, including the methicillin-resistant Staphylococcus aureus (MRSA) represent a serious medical problem. The search for new antiinfectives, possessing a diverse mechanism of action compared to the clinically used antibiotics, has become an attractive research field. S. aureus DNA encodes a β-class carbonic anhydrase, SauBCA. It is a druggable target that can be inhibited by certain aromatic and heterocyclic sulphonamides. Here we investigated inorg...