Ceragenins exhibiting promising antimicrobial activity against various multidrug resistant Gram negative bacteria

Abstract

DOI: 10.26650/IstanbulJPharm.2018.400730

Ceragenins are novel promising agents for the treatment of infections caused by multi-drug resistant microorganisms. Since colistin resistance has become a worldwide problem, the need for new treatment agents has been increasing steadily. Therefore, this study aimed to investigate in vitro antimicrobial activities of ceragenins (Cationic Steroid Antibiotics) (CSA-8, CSA-13, CSA-142 and CSA-192) against multidrug resistant Gram negative isolates from Turkey. Experiments were performed by using broth microdilution method against Klebsiella pneumoniae, Morganella morganii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia isolates. All microorganisms except for three isolates were identified as multidrug resistant. Among tested ceragenins, CSA-13 showed the best results (MIC: 8-64 µg/ml). Nevertheless, the antimicrobial activity of CSA-8 was not significant. In conclusion, ceragenins appear to be a good candidate as antimicrobial therapy in the presence of multidrug (including colistin) resistant microorganisms.

Keywords

• Ceragenins,colistin resistance,gram negative pathogens

References

1. Ah YM, Kim AJ, Lee JY (2014). Colistin resistance in Klebsiella pneumoniae. Int J Antimicrob Agents, 44(1): 8-15.
2. Band VI, Weiss DS (2014). Mechanisms of antimicrobial peptide resistance in Gram-negative bacteria. Antibiot, 4(1): 18-41.
3. Bolla JM, Alibert-Franco S, Handzlik J, Chevalier J, Mahamoud A, Boyer G, Kieć-Kononowicz K (2011). Strategies for bypassing the membrane barrier in multidrug resistant Gram‐negative bacteria. FEBS lett, 585(11): 1682-1690.
4. Bozkurt-Guzel C, Savage PB, Akcali A, Ozbek-Celik B (2014). Potential synergy activity of the novel ceragenin, CSA-13, against carbapenem-resistant Acinetobacter baumannii strains isolated from bacteremia patients. Biomed Res Int, 2014: 710273.
5. Bozkurt-Güzel Ç, Tüysüz M, İnan N, & Savage PB (2014). Katyonik steroid antibiyotiklerden olan CSA-8, CSA-13, CSA-44, CSA-131 ve CSA-138’in, kan kültürlerinden izole edilen Candida albicans suşlarına karşı antifungal etkilerinin araştırılması. Ankem Derg, 28(1): 8-13.
6. Chin JN, Jones RN, Sader HS, Savage PB, Rybak MJ (2007). Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa. J Antimicrob Chemother, 61(2): 365-370.
7. Döşler, S (2017). Antimicrobial peptides: Coming to the end of antibiotic era, the most promising agents. Istanbul J Pharm, 47(2): 72-76.
8. Durnaś B, Wnorowska U, Pogoda K, Deptuła P, Wątek M, Piktel E (2016). Candidacidal activity of selected ceragenins and human cathelicidin LL-37 in experimental settings mimicking infection sites. PloS one,11(6): e0157242.

9. Durnaś B, Wnorowska U, Pogoda K, Deptuła P, Wątek M, Piktel E, Bucki R (2016). Candidacidal activity of selected ceragenins and human cathelicidin LL-37 in experimental settings mimicking infection sites. PloS one, 11(6): e0157242.
10. Guan Q LC, Schmidt EJ, Boswell JS, Walsh JP, Allman GW (2000). Preparation and Characterization of Cholic Acid-Derived Antimicrobial Agents with Controlled Stabilities. Org lett, 2(18): 2837-40.
11. Hashemi MM, Rovig J, Weber S, Hilton B, Forouzan MM, Savage PB (2017). Susceptibility of colistin-resistant, Gram-negative bacteria to antimicrobial peptides and ceragenins. Antimicrob Agents Chemother, 61: e00292-17.
12. International Organization for Standards. 15 November 2006, posting date. Susceptibility testing of infectious agents and evaluation of performance of antimicrobial susceptibility testing devices. 1. Reference method for testing the in vitro activity of antimicrobial agents against rapidly growing anaerobic bacteria involved in infectious diseases. ISO 20776-1. International Organization for Standards, Geneva, Switzerland.
13. Lai XZ, Feng Y, Pollard J, Chin JN, Rybak MJ, Bucki R, Epand RF, Epand RM, Savage PB (2008). Ceragenins: cholic acid-based mimics of antimicrobial peptides. Acc Chem Res, 41(10): 1233-1240.
14. Leszczyńska K, Namiot D, Byfield FJ, Cruz K, Zendzian-Piotrowska M, Fein DE, Savage PB, Diamond S, McCulloch CA, Janmey PA, Bucki R (2013). Antibacterial activity of the human host defence peptide LL-37 and selected synthetic cationic lipids against bacteria associated with oral and upper respiratory tract infections. J Antimicrob Chemother, 68: 610-618.
15. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Paterson DL (2012). Multidrug‐resistant, extensively drug‐resistant and pandrug‐resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect, 18(3): 268-281.
16. Marchaim D, Chopra T, Pogue JM, Perez F, Hujer AM, Rudin S, Endimiani A, Navon-Venezia S, Hothi J, Slim J, Blunden, C (2011). Outbreak of colistin-resistant, carbapenem-resistant Klebsiella pneumoniae in metropolitan Detroit, Michigan. Antimicrob Agents Chemother, 55(2): 593-599.
17. Olekson MA, You T, Savage PB, Leung KP (2017). Antimicrobial ceragenins inhibit biofilms and affect mammalian cell viability and migration in vitro. FEBS Open Bio, 7(7): 953-967.
18. Otter JA, Doumith M, Davies F, Mookerjee S, Dyakova E, Gilchrist M, Brannigan ET, Bamford K, Galletly T, Donaldson H, Aanensen DM, Ellington MJ, Hill R, Turton JF, Hopkins KL, Woodford N, Holmes A, Aanensen DM (2017). Emergence and clonal spread of colistin resistance due to multiple mutational mechanisms in carbapenemase-producing Klebsiella pneumoniae in London. Sci Rep, 7(1): 12711.
19. Pollard JE, Snarr J, Chaudhary V, Jennings JD, Shaw H, Christiansen B, Wright J, Jia W, Bishop RE, Savage PB (2012). In vitro evaluation of the potential for resistance development to ceragenin CSA-13. J Antimicrob Chemother, 67(11): 2665-2672.
20. Rojas LJ, Salim M, Cober E, Richter SS, Perez F, Salata RA, Kalayjian RC, Watkins RR, Marshall S, Rudin SD, Domitrovic TN, Hujer AM, Hujer KM, Doi Y, Kaye K, Evans S, Fowler VG, Bonomo RA (2016). Colistin resistance in carbapenem-resistant Klebsiella pneumoniae: laboratory detection and impact on mortality. Clin Infect Dis, 64(6): 711-718.
21. Rossi F, Girardello R, Cury AP, Di Gioia TSR, Almeida JND, Duarte AJDS (2017). Emergence of colistin resistance in the largest university hospital complex of São Paulo, Brazil, over five years. Braz J Infect Dis, 21(1): 98-101.
22. Saha S, Savage PB, Bal M (2008). Enhancement of the efficacy of erythromycin in multiple antibiotic‐resistant Gram‐negative bacterial pathogens. J Appl Microbiol, 105(3): 822-828.
23. Sonnevend Á, Ghazawi A, Alqahtani M, Shibl A, Jamal W, Hashmey R, Pal T (2016). Plasmid-mediated colistin resistance in Escherichia coli from the Arabian Peninsula. Int J Infect Dis, 50: 85-90.
24. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2018). Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0. http://www.eucast.org
25. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2018). Routine and extended internal quality control for MIC determination and disk diffusion as recommended by EUCAST. Version 8.0. http://www.eucast.org
26. Vila-Farrés X, Callarisa AE, Gu X, Savage PB, Giralt E, Vila J (2015). CSA-131, a ceragenin active against colistin-resistant Acinetobacter baumannii and Pseudomonas aeruginosa clinical isolates. Int J Antimicrob Agents, 46(5): 568-571.
27. World Health Organization (WHO) (2017). Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization.
28. Zaman SB, Hussain MA, Nye R, Mehta V, Mamun KT, Hossain N (2017). A review on antibiotic resistance: alarm bells are ringing. Cureus, 9(6): e1403.