Recent developments of agents targeting Vibrio cholerae : patents and literature data

Authors: Francesco Melfi; Simone Carradori; Noemi Mencarelli; Cristina Campestre; Arianna Granese; Mattia Mori doi:10.1080/13543776.2024.2327305

ABSTRACT

Introduction 

Vibrio cholerae bacteria cause an infection characterized by acute diarrheal illness in the intestine. Cholera is sustained by people swallowing contaminated food or water. Even though symptoms can be mild, if untreated disease becomes severe and life-threatening, especially in low-income countries.

Areas covered 

After a description of the most recent literature on the pathophysiology of this infection, we searched for patents and literature articles following the PRISMA guidelines, filtering the results disclosed from 2020 to present. Moreover, some innovative molecular targets (e.g., carbonic anhydrases) and pathways to counteract this rising problem were also discussed in terms of design, structure-activity relationships and structural analyses.

Expert opinion 

This review aims to cover and analyze the most recent advances on the new druggable targets and bioactive compounds against this fastidious pathogen, overcoming the use of old antibiotics which currently suffer from high resistance rate.

Graphical abstract

KEYWORDS: 

Article highlights

  • V. cholerae infections are usually treated by an arsenal of old drugs.
  • Selective inhibitors of V. cholerae carbonic anhydrases are making a splash.
  • New compounds or formulations can target biofilm formation and eradication.
  • Aspartate-semialdehyde dehydrogenase is inhibited by heptapeptide inhibitors.
  • Tyrosol acetate and tryptophol acetate act as inhibitors of Quorum Sensing in V. cholerae.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewers on this manuscript received an honorarium from Expert Opinion on Therapeutic Patents for their review work but have no other relevant financial relationships to disclose. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Authors contribution statement

F.M., C.C., and N.M. searched for the literature, S.C. and A.G. filtered the search results, M.M. analyzed the biological targets in silico. All the authors read and approved the final version of the manuscript.

Additional information

Funding

This research was partially supported by the Italian Ministry for University and Research (MIUR) grant number FISR2019_04819 BacCAD to S.C. This article is based upon work from COST Action EURESTOP, CA21145, supported by COST (European Cooperation in Science and Technology). This research was supported by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT).

References

  • Ramamurthy T, Nandy RK, Mukhopadhyay AK, et al. Virulence regulation and innate host response in the pathogenicity of Vibrio cholerae. Front Cell Infect Microbiol. 2020;10:572096. doi: 10.3389/fcimb.2020.572096 
  • Hsiao A, Zhu J. Pathogenicity and virulence regulation of Vibrio cholerae at the interface of host-gut microbiome interactions. Virulence. 2020;11(1):1582–1599. doi: 10.1080/21505594.2020.1845039 
  • Alam M, Sultana M, Nair GB, et al. Toxigenic vibrio cholerae in the aquatic environment of Mathbaria, Bangladesh. Appl Environ Microbiol. 2006;72(4):2849–55. doi: 10.1128/AEM.72.4.2849-2855.2006 
  • Faruque SM, Albert MJ, Mekalanos JJ. Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae. Microbiol Mol Biol Rev. 1998;62(4):1301–1314. doi: 10.1128/MMBR.62.4.1301-1314.1998 
  • WHO. Cholera annual report 2017. Weekly Epidemiological Rec. 2018;93:489–500. Google Scholar
  • Ramamurthy T, Yamasaki S, Takeda Y, et al. Vibrio cholerae O139 Bengal: odyssey of a fortuitous variant. Microbes Infect. 2003 5;5(4):329–344. doi: 10.1016/S1286-4579(03)00035-2 
  • Kaper JB, JG M Jr., Levine MM. Cholera. Clin Microbiol Rev. 1995;8:48–86. doi: 10.1128/CMR.8.1.48 
  • Watnick PI, Kolter R. Steps in the development of a vibrio cholerae El tor biofilm. Mol Microbiol. 1999;34(3):586–595. doi: 10.1046/j.1365-2958.1999.01624.x 
  • Grande R, Puca V, Muraro R. Antibiotic resistance and bacterial biofilm. Expert Opin Ther Pat. 2020;30(12):897–900. doi: 10.1080/13543776.2020.1830060 
  • Thelin KH, Taylor RK. Toxin-coregulated pilus, but not mannose-sensitive hemagglutinin, is required for colonization by vibrio cholerae O1 El tor biotype and O139 strains. Infect Immun. 1996;64(7):2853–2856. doi: 10.1128/iai.64.7.2853-2856.1996 
  • [cited 11 Oct 2023]. Available from: https://www.who.int/news-room/fact-sheets/detail/cholera
  • Bitar A, Aung KM, Wai SN, et al. Vibrio cholerae derived outer membrane vesicles modulate the inflammatory response of human intestinal epithelial cells by inducing microRNA-146a. Sci Rep. 2019;9(1):7212. doi: 10.1038/s41598-019-43691-9 
  • Verma J, Bag S, Saha B, et al. Genomic plasticity associated with antimicrobial resistance in Vibrio cholerae. Proc Natl Acad Sci, USA. 2019;116(13):6226–6231. doi: 10.1073/pnas.1900141116 
  • Das B, Verma J, Kumar P, et al. Antibiotic resistance in Vibrio cholerae: understanding the ecology of resistance genes and mechanisms. Vaccine. 2020;38 Suppl 1:A83–A92. doi: 10.1016/j.vaccine.2019.06.031 
  • Reimann HA, Chang GC, Chu L-W, et al. Asiatic cholera; clinical study and experimental therapy with streptomycin. Am J Trop Med Hyg. 1946;26:631–647. doi: 10.4269/ajtmh.1946.s1-26.631 
  • Uylangco CV, Fabie AE, Mier SG, et al. Oral streptomycin in the treatment of cholera. J Philipp Med Assoc. 1965;41:763–769. Google Scholar
  • Chaudhuri RN, Ghosal S, Rai Chaudhuri MN. Chloromycetin in the treatment of cholera. Ind Med Gaz. 1950;85:398–400. Google Scholar
  • Chakravarti HS, Mondal A, Mukherjee AM, et al. Further observations on intravenous chloramphenicol in cholera. J Indian Med Assoc. 1954;23:331–332. Google Scholar
  • Karchmer AW, Curlin GT, Huq MI, et al. Furazolidone in paediatric cholera. Bull World Health Organ. 1970;43:373–378. Google Scholar
  • Grados P, Bravo N, Battilana C. Comparative effectiveness of co-trimoxazole and tetracycline in the treatment of cholera. Bull Pan Am Health Organ. 1996;30:36–42. Google Scholar
  • Gharagozloo RA, Naficy K, Mouin M, et al. Comparative trial of tetracycline, chloramphenicol, and trimethoprim-sulphamethoxazole in eradication of Vibrio cholerae El Tor. Br Med J. 1970;4(5730):281–282. doi: 10.1136/bmj.4.5730.281 
  • Pastore G, Rizzo G, Fera G, et al. Trimethoprim-sulphamethoxazole in the treatment of cholera. Comparison with tetracycline and chloramphenicol. Chemotherapy. 1977;23(2):121–128. doi: 10.1159/000221980 
  • Dutta JK, Santhanam S, Misra BS, et al. Effect of trimethoprim-sulphamethoxazole on vibrio clearance in cholera (El tor): a comparative study. Trans R Soc Trop Med Hyg. 1978;72(1):40–42. doi: 10.1016/0035-9203(78)90297-3 
  • Aminov RI, Mackie RI. Evolution and ecology of antibiotic resistance genes. FEMS Microbiol Lett. 2007;271(2):147–161. doi: 10.1111/j.1574-6968.2007.00757.x 
  • Mhalu FS, Mmari PW, Ijumba J. Rapid emergence of El Tor Vibrio cholerae resistant to antimicrobial agents during first six months of fourth cholera epidemic in Tanzania. Lancet. 1979;1(8112):345–347. doi: 10.1016/S0140-6736(79)92889-7 
  • Yu L, Zhou Y, Wang R, et al. Multiple antibiotic resistance of Vibrio cholerae serogroup O139 in China from 1993 to 2009. PLoS One. 2012;7(6):e38633. doi: 10.1371/journal.pone.0038633 
  • Yuan XH, Li YM, Vaziri AZ, et al. Global status of antimicrobial resistance among environmental isolates of Vibrio cholerae O1/O139: a systematic review and meta-analysis. Antimicrob Resist Infect Control. 2022;11(1):62. doi: 10.1186/s13756-022-01100-3 
  • Mohammed Y, Aboderin AO, Okeke IN, et al. Antimicrobial resistance of Vibrio cholerae from sub-Saharan Africa: a systematic review. Afr J Lab Med. 2018;7(2):778. doi: 10.4102/ajlm.v7i2.778 
  • Moher D, Liberati A, Tetzlaff J. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097 
  • Abuaita BH, Withey JH. Bicarbonate induces vibrio cholerae virulence gene expression by enhancing ToxT activity. Infect Immun. 2009;77(9):4111–4120. doi: 10.1128/IAI.00409-09 
  • Zeller T, Klug G. Thioredoxins in bacteria: functions in oxidative stress response and regulation of thioredoxin genes. Naturwissenschaften. 2006;93(6):259–266. doi: 10.1007/s00114-006-0106-1 
  • Supuran CT. Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas. Expert Opin Ther Pat. 2018;28(10):709–712. doi: 10.1080/13543776.2018.1523897 
  • Capasso C, Supuran CT. Bacterial, fungal and protozoan carbonic anhydrases as drug targets, expert opinion on therapeutic targets. 2015;19(12):1689–1704. doi: 10.1517/14728222.2015.1067685 
  • Del Prete S, Isik S, Vullo D, et al. DNA cloning, characterization, and inhibition studies of an α-carbonic anhydrase from the pathogenic bacterium vibrio cholerae. J Med Chem. 2012;55(23):10742–8. doi: 10.1021/jm301611m 
  • Supuran CT. A simple yet multifaceted 90 years old, evergreen enzyme: carbonic anhydrase, its inhibition and activation. Bioorg Med Chem Lett. 2023;93:129411. doi: 10.1016/j.bmcl.2023.129411 
  • Vullo D, Del Prete S, De Luca V, et al. Anion inhibition studies of the b-carbonic anhydrase from the pathogenic bacterium vibrio cholerae. Bioorg Med Chem Lett. 2016;26(5):1406–1410. doi: 10.1016/j.bmcl.2016.01.072 
  • Supuran CT. An overview of novel antimicrobial carbonic anhydrase inhibitors. Expert Opin Ther Targets. 2023;27(10):1–14. doi: 10.1080/14728222.2023.2263914 
  • Mancuso F, De Luca L, Bucolo F, et al. 4-sulfamoylphenylalkylamides as inhibitors of carbonic anhydrases expressed in Vibrio cholerae. ChemMedchem. 2021;16(24):3787–94. doi: 10.1002/cmdc.202100510 
  • Ali M, Angeli A, Bozdag M, et al. Benzylaminoethylureido-tailed benzenesulfonamides show potent inhibitory activity against bacterial carbonic anhydrases. ChemMedchem. 2020;15(24):2444–7. doi: 10.1002/cmdc.202000680 
  • Carradori S, Ammazzalorso A, Niccolai S, et al. Nature-inspired compounds: synthesis and antibacterial susceptibility testing of eugenol derivatives against H. pylori Strains. Pharmaceuticals. 2023;16(9):1317. doi: 10.3390/ph16091317 
  • Nogueira CW, Barbosa NV, Rocha JBT. Toxicology and pharmacology of synthetic organoselenium compounds: an update. Arch Toxicol. 2021;95(4):1179–1226. doi: 10.1007/s00204-021-03003-5 
  • Angeli A, Pinteala M, Maier SS, et al. Evaluation of thio- and seleno-acetamides bearing benzenesulfonamide as inhibitor of carbonic anhydrases from different pathogenic bacteria. Int J Mol Sci. 2020;21(2):598. doi: 10.3390/ijms21020598 
  • Mancuso F, Angeli A, De Luca V, et al. Synthesis and biological evaluation of sulfonamide-based compounds as inhibitors of carbonic anhydrase from Vibrio cholerae. Arch Pharm. 2022;355(10):e2200070. doi: 10.1002/ardp.202200070 
  • Akgul O, Angeli A, Selleri S, et al. Taurultams incorporating arylsulfonamide: first in vitro inhibition studies of α-, β- and γ-class carbonic anhydrases from Vibrio cholerae and Burkholderia pseudomallei. Eur J Med Chem. 2021;219:113444. doi: 10.1016/j.ejmech.2021.113444 
  • Fantacuzzi M, D’Agostino I, Carradori S, et al. Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships. J Enzyme Inhib Med Chem. 2023;38(1):2201402. doi: 10.1080/14756366.2023.2201402 
  • Jacob GS, Brown RD 3rd, Koenig SH. Interaction of bovine carbonic anhydrase with (neutral) aniline, phenol, and methanol. Biochemistry. 1980;19(16):3754–3765. doi: 10.1021/bi00557a017 
  • Simonsson I, Jonsson BH, Lindskog S. Phenol, a competitive inhibitor of CO2 hydration catalyzed by carbonic anhydrase. Biochem Biophys Res Commun. 1982;108(4):1406–1412. doi: 10.1016/S0006-291X(82)80063-6 
  • Nair SK, Ludwig PA, Christianson DW. Two-site binding of phenol in the active site of human carbonic anhydrase II: structural implications for substrate association. J Am Chem Soc. 1994;116(8):3659–3660. doi: 10.1021/ja00087a086 
  • Giovannuzzi S, Hewitt CS, Nocentini A, et al. Inhibition studies of bacterial α-carbonic anhydrases with phenols. J Enzyme Inhib Med Chem. 2022;37(1):666–671. doi: 10.1080/14756366.2022.2038592 
  • Giovannuzzi S, Hewitt CS, Nocentini A, et al. Coumarins effectively inhibit bacterial α-carbonic anhydrases. J Enzyme Inhib Med Chem. 2022;37(1):333–338. doi: 10.1080/14756366.2021.2012174 
  • Bonardi A, Nocentini A, Cadoni R, et al. Benzoxaboroles: new potent inhibitors of the carbonic anhydrases of the pathogenic bacterium vibrio cholerae. ACS Med Chem Lett. 2020;11(11):2277–2284. 
  • The Reagents of the University of Michigan. Mitochondrial targeting compounds for the treatment of associated diseases. WO 2021/242753 A1. Google Scholar
  • University of North Carolina at Wilmington, The University of Toledo. Compounds having selective inactivation activity. WOr̥ 2023/003882 A2. Google Scholar
  • Gao G, Liu X, Pavlovsky A, et al. Identification of selective enzyme inhibitors by fragment library screening. J Biomol Screen. 2010;15(9):1042–50. doi: 10.1177/1087057110381383 
  • Blanco J, Moore RA, Kabaleeswaran V, et al. A structural basis for the mechanism of aspartate-beta-semialdehyde dehydrogenase from Vibrio cholerae. Protein Sci. 2003;12(1):27–33. doi: 10.1110/ps.0230803 
  • Technische Universiteit Eindhoven. Peptides for use in the treatment of cholera. WO 2021/010835 A1. Google Scholar
  • Kitts G, Giglio KM, Zamorano-Sánchez D, et al. A conserved regulatory circuit controls large adhesins in Vibrio cholerae. MBio. 2019;10(6):e02822–19. doi: 10.1128/mBio.02822-19 
  • Ruiz VL, Robert J. The amphibian immune system. Philos Trans R Soc Lond B Biol Sci. 2023;378(1882):20220123. doi: 10.1098/rstb.2022.0123 
  • Kumar KS. Therapeutic compositions of antimicrobial peptides. WO2019077634 A2. Google Scholar
  • Technische Universitat Wien. Methods, apparatus and kits for bacterial cell lysis. WO 2020/094674 A1. Google Scholar
  • Bosire EM, Eade CR, Schiltz CJ, et al. Diffusible signal factors act through AraC-type transcriptional regulators as chemical cues to repress virulence of enteric pathogens. Infect Immun. 2020;88(10):e00226–20. doi: 10.1128/IAI.00226-20 
  • Carradori S, Di Giacomo N, Lobefalo M, et al. Biofilm and quorum sensing inhibitors: the road so far. Expert Opin Ther Pat. 2020;30(12):917–930. doi: 10.1080/13543776.2020.1830059 
  • Cornell University. Compositions and methods for inhibiting vibrio infection. WO 2021/202632 A2. Google Scholar
  • Council of Scientific & Industrial Research. Anti-virulence formulation from microalgal lipids against Vibrio cholerae and process for the preparation thereof. IN 2019/11011645 A. Google Scholar
  • G B. Negev Technologies and applications LTD., at Ben Gurion University. Microorganism mixtures, molecules derived therefrom, and methods of use thereof. WO 2020/031191 A1. Google Scholar
  • Swapnil Pradip L, Bela Mangesh N. Anti-biofilm compositions and preparations methods thereof. IN 2018/21043415 A. Google Scholar
  • The Ospital For Sick Children, CA. Compositions and methods for protecting a host from enteric toxigenic pathogens. CA 3013606 A1. Google Scholar
  • The Wistar Institute. IspH inhibitors, and methods of making and using same. WO 2021/021933 A1. Google Scholar
  • Indian Council Of Medical Research. Composition for management of vibrio cholerae induced diarrhea. IN2020/11054354 A. Google Scholar
  • Ferraroni M, Del Prete S, Vullo D, et al. Crystal structure and kinetic studies of a tetrameric type II β-carbonic anhydrase from the pathogenic bacterium vibrio cholerae. Acta Crystallogr D Biol Crystallogr. 2015;71(Pt 12):2449–2456. 
  • Viola RE, Liu X, Ohren JF, et al. The structure of a redundant enzyme: a second isoform of aspartate beta-semialdehyde dehydrogenase in Vibrio cholerae. Acta Crystallogr D Biol Crystallogr. 2008;64(Pt 3):321–330. doi: 10.1107/S0907444907068552 
  • The Children’s Medical Center Corporation. Vaccines, compositions and methods for use thereof to prevent or reduce severity of cholera. US 2020/0030431 Al. Google Scholar
  • Wai SNU, Eric Nadeem B, Aftab Persson K Vibrio cholerae protein for use against cancer. WO 2021/071419 Al. Google Scholar
  • Livinguard AG. Textiles having antimicrobial properties. EP 3812506 A1. Google Scholar