Generic placeholder image

Current Drug Discovery Technologies


ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

Identification and Ranking of Clinical Compounds with Activity Against Log-phase Growing Uropathogenic Escherichia coli

Author(s): Hongxia Niu, Rebecca Yee, Peng Cui, Shuo Zhang, Lili Tian, Wanliang Shi, David Sullivan, Bingdong Zhu, Wenhong Zhang and Ying Zhang *

Volume 17, Issue 2, 2020

Page: [191 - 196] Pages: 6

DOI: 10.2174/1570163815666180808115501

Price: $65


Background: Uropathogenic Escherichia coli (UPEC) is a major cause of Urinary Tract Infections (UTIs). Due to increasing antibiotic-resistance among UPEC bacteria, new treatment options for UTIs are urgently needed.

Objective: To identify new agents targeting growing bacteria that may be used for the treatment of antibiotic-resistant UTIs.

Methods: We screened a clinical compound library consisting of 1,524 compounds using a high throughput 96-well plate assay and ranked the activities of the selected agents according to their MICs against the UPEC strain UTI89.

Results: We identified 33 antibiotics which were active against log-phase clinical UPEC strain UTI89. Among the selected antibiotics, there were 12 fluoroquinolone antibiotics (tosufloxacin, levofloxacin, sparfloxacin, clinafloxacin, pazufloxacin, gatifloxacin, enrofloxacin, lomefloxacin, norfloxacin, fleroxacin, flumequine, ciprofloxacin), 15 beta-lactam or cephalosporin antibiotics (cefmenoxime, cefotaxime, ceftizoxime, cefotiam, cefdinir, cefoperazone, cefpiramide, cefamandole, cefixime, ceftibuten, cefmetazole, cephalosporin C, aztreonam, piperacillintazobactam, mezlocillin), 3 tetracycline antibiotics (meclocycline, doxycycline, tetracycline), 2 membrane-acting agents (colistin and clofoctol), and 1 protein synthesis inhibitor (amikacin). Among them, the top 7 hits were colistin, tosufloxacin, levofloxacin, sparfloxacin, clinafloxacin, cefmenoxime and pazufloxacin, where clinafloxacin and pazufloxacin were the newly identified agents active against UPEC strain UTI89. We validated the key results obtained with UTI89 on two other UTI strains CFT073 and KTE181 and found that they all had comparable MICs for fluoroquinolones while CFT073 and KTE181 were more susceptible to cephalosporin antibiotics and tetracycline antibiotics but were less susceptible to colistin than UTI89.

Conclusion: Our findings provide possible effective drug candidates for the more effective treatment of antibiotic-resistant UTIs.

Keywords: Log-phase, uropathogenic Escherichia coli, UTIs, clinical compound library, urinary tract infection, colistin.

Graphical Abstract
Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients. Arch Intern Med 2000; 160(5): 678-82.
[PMID: 10724054]
Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol 2010; 7(12): 653-60.
[] [PMID: 21139641]
Johnson CC. Definitions, classification, and clinical presentation of urinary tract infections. Med Clin North Am 1991; 75(2): 241-52.
[] [PMID: 1996031]
Kline KA, Schwartz DJ, Lewis WG, Hultgren SJ, Lewis AL. Immune activation and suppression by group B streptococcus in a murine model of urinary tract infection. Infection and Immunity 2011; 79(9): 3588-95.
Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Am J Med 2002; 113(Suppl. 1A): 14S-9S.
[] [PMID: 12113867]
Fisher JF, Kavanagh K, Sobel JD, Kauffman CA, Newman CA. Candida urinary tract infection: pathogenesis. Clin Infect Dis 2011; 52(Suppl. 6): S437-51.
[] [PMID: 21498837]
Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015; 13(5): 269-84.
[] [PMID: 25853778]
Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011; 52(5): e103-20.
[] [PMID: 21292654]
Wang Y, Zhao S, Han L, et al. Drug resistance and virulence of uropathogenic Escherichia coli from Shanghai, China. J Antibiot (Tokyo) 2014; 67(12): 799-805.
[] [PMID: 24984795]
Molina-López J, Aparicio-Ozores G, Ribas-Aparicio RM, et al. Drug resistance, serotypes, and phylogenetic groups among uropathogenic Escherichia coli including O25-ST131 in Mexico City. J Infect Dev Ctries 2011; 5(12): 840-9.
[] [PMID: 22169782]
Bashir S, Sarwar Y, Ali A, Mohsin M, Saeed MA, Tariq A, et al. Multiple drug resistance patterns in various phylogenetic groups of uropathogenic E.coli isolated from Faisalabad region of Pakistan. Brazilian Journal of Microbiology: [publication of the Brazilian Society for Microbiology] 2011; 42(4): 1278-83.
[] [PMID: 24031752]
Zhang Y. Persisters, persistent infections and the Yin-Yang model. Emerg Microbes Infect 2014; 3(1)e3
[] [PMID: 26038493]
Niu H, Cui P, Shi W, et al. Identification of Anti-Persister Activity against Uropathogenic Escherichia coli from a Clinical Drug Library. Antibiotics (Basel) 2015; 4(2): 179-87.
[] [PMID: 27025620]
Chen SL, Hung CS, Xu J, et al. Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: a comparative genomics approach. Proc Natl Acad Sci USA 2006; 103(15): 5977-82.
[] [PMID: 16585510]
Mavromatis C, Bokil NJ, Totsika M, et al. The co-transcriptome of uropathogenic Escherichia coli-infected mouse macrophages reveals new insights into host-pathogen interactions. Cell Microbiol 2015; 17(5): 730-46.
[] [PMID: WOS:000353051400010]
Blango MG, Mulvey MA. Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrobial Agents andChemotherapy 2010; 54(5): 1855-63.
Niu H, Cui P, Yee R, et al. A clinical drug library screen identifies tosufloxacin as being highly active against Staphylococcus aureus persisters. Antibiotics (Basel) 2015; 4(3): 329-36.
[] [PMID: 27025627]
Chong CR, Chen XC, Shi LR. A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol 2006; 2(8): 415-6.
[] [PMID: WOS:000239146800009]
Niu H, Yee R, Cui P, et al. Identification of Agents Active against Methicillin-Resistant Staphylococcus aureus USA300 from a Clinical Compound Library. Pathogens 2017; 6(3)E44
[] [PMID: 28930155]
Suzuki K, Nagata Y. [Clinical efficacy of T-3262, a new quinolone compound, on urinary tract infection in 1988]. Hinyokika Kiyo 1989; 35(4): 717-26. [Clinical efficacy of T-3262, a new quinolone compound, on urinary tract infection in 1988].
[PMID: 2735274]
Fleming E, Heil EL, Hynicka LM. Treatment strategy for a multidrug-resistant Klebsiella UTI. Ann Pharmacother 2014; 48(1): 123-7.
[] [PMID: 24259631]
Cui P, Niu H, Shi W, et al. Disruption of Membrane by Colistin Kills Uropathogenic Escherichia coli Persisters and Enhances Killing of Other Antibiotics. Antimicrob Agents Chemother 2016; 60(11): 6867-71.
[] [PMID: 27600051]
Maekawa M, Takahashi K, Takahata M, Minami S. [In vitro combination effect of pazufloxacin with various antibiotics against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus]. Jpn J Antibiot 2002; 55(4): 440-5.
[PMID: 12378872]
Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs 2002; 62(1): 13-59.
[] [PMID: 11790155]
Yoshida K, Kobayashi N, Saitoh H, et al. [Clinical efficacy of tosufloxacin on the patients with urinary tract infections]. Hinyokika Kiyo 1992; 38(1): 129-34.
[PMID: 1546562]
Tokura Y, Iwamoto Y, Mizutani K, Takigawa M. Sparfloxacin phototoxicity: potential photoaugmentation by ultraviolet A and B sources. Arch Dermatol Res 1996; 288(1): 45-50.
[] [PMID: 8750934]
Sirijatuphat R, Limmahakhun S, Sirivatanauksorn V, Nation RL, Li J, Thamlikitkul V. Preliminary clinical study of the effect of ascorbic acid on colistin-associated nephrotoxicity. Antimicrob Agents Chemother 2015; 59(6): 3224-32.
[] [PMID: 25801556]
Zhang Y, Wade MM, Scorpio A, Zhang H, Sun Z. Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 2003; 52(5): 790-5.
[] [PMID: 14563891]
Hurdle JG, O’Neill AJ, Chopra I, Lee RE. Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 2011; 9(1): 62-75.
[] [PMID: 21164535]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy