In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine

BackgroundSeveral antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics.MethodsTigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falciparum alone and in combination with CQ. Tigecycline was also tested in vivo in combination with CQ in Plasmodium berghei-mouse malaria model for parasitaemia suppression, survival and cure of the malaria infection.ResultsTigecycline was significantly more active against CQ-resistant (W2) than CQ-susceptible (D6) strain of P. falciparum. Tigecycline potentiated the anti-malarial action of CQ against the CQ-resistant strain of P. falciparum by more than seven-fold. Further, treatment of mice infected with P. berghei with tigecycline (ip) produced significant suppression in parasitaemia development and also prolonged the mean survival time. Treatment with as low as 3.7 mg/kg dose of tigecycline, once daily for four days, produced 77-91% suppression in parasitaemia. In vivo treatment with tigecycline in combination with subcurative doses of CQ produced complete cure in P. berghei-infected mice.ConclusionResults indicate prominent anti-malarial action of tigecycline in vitro and in vivo in combination with CQ and support further evaluation of tigecycline as a potential combination candidate for treatment of drug-resistant cases of malaria.

[1]  D. Mazel,et al.  Antibiotics, Present and Future , 1999 .

[2]  M. Schlitzer,et al.  Antibiotics in malaria therapy and their effect on the parasite apicoplast. , 2010, Current molecular medicine.

[3]  R. Piper,et al.  Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity. , 1993, The American journal of tropical medicine and hygiene.

[4]  Lucélia Magalhães da Silva,et al.  Tigecycline: A Review of Properties, Applications, and Analytical Methods , 2010, Therapeutic drug monitoring.

[5]  W. A. Khan,et al.  Antimalarial Activity of Tigecycline, a Novel Glycylcycline Antibiotic , 2009, Antimicrobial Agents and Chemotherapy.

[6]  D. Fidock,et al.  In Vitro Efficacy, Resistance Selection, and Structural Modeling Studies Implicate the Malarial Parasite Apicoplast as the Target of Azithromycin* , 2007, Journal of Biological Chemistry.

[7]  M. Schlitzer,et al.  Telithromycin and Quinupristin-Dalfopristin Induce Delayed Death in Plasmodium falciparum , 2007, Antimicrobial Agents and Chemotherapy.

[8]  R. Kast.  Minocycline in cerebral malaria , 2008, Journal of Neuroscience Research.

[9]  A. Magill,et al.  Doxycycline for Malaria Chemoprophylaxis and Treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis , 2011, The American journal of tropical medicine and hygiene.

[10]  B. Tekwani,et al.  Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs , 2009, Antimicrobial Agents and Chemotherapy.

[11]  L. C. Koontz,et al.  Plasmodium berghei: development of resistance to clindamycin and minocycline in mice. , 1976, Experimental parasitology.

[12]  Nobhojit Roy,et al.  Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2014, The Lancet.

[13]  K. Matuschewski,et al.  Natural Immunization Against Malaria: Causal Prophylaxis with Antibiotics , 2010, Science Translational Medicine.

[14]  P. Rosenthal,et al.  Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast , 2007, Antimicrobial Agents and Chemotherapy.

[15]  Daniel S. Terry,et al.  Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis , 2013, Proceedings of the National Academy of Sciences.

[16]  H. R. Salgado,et al.  Tigecycline: a review of properties, applications, and analytical methods , 2010 .

[17]  P. Rosenthal.  The interplay between drug resistance and fitness in malaria parasites , 2013, Molecular microbiology.

[18]  P. Schlagenhauf,et al.  Risk factors associated with malaria deaths in travellers: a literature review. , 2015, Travel medicine and infectious disease.

[19]  A. MacGowan,et al.  Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. , 2006, The Journal of antimicrobial chemotherapy.

[20]  C. Obonyo,et al.  Clindamycin plus quinine for treating uncomplicated falciparum malaria: a systematic review and meta-analysis , 2012, Malaria Journal.

[21]  B. Tekwani,et al.  Growth, Drug Susceptibility, and Gene Expression Profiling of Plasmodium falciparum Cultured in Medium Supplemented with Human Serum , 2007, Journal of biomolecular screening.

[22]  E. Klein.  Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread. , 2013, International journal of antimicrobial agents.

[23]  B. Mordmüller,et al.  In vitro activity of tigecycline in Plasmodium falciparum culture-adapted strains and clinical isolates from Gabon. , 2010, International journal of antimicrobial agents.

[24]  P. Magnussen,et al.  Antibiotic use among patients with febrile illness in a low malaria endemicity setting in Uganda , 2011, Malaria Journal.

[25]  D. Terlouw,et al.  Azithromycin for treating uncomplicated malaria. , 2011, The Cochrane database of systematic reviews.

[26]  J. Gut,et al.  In Vitro and In Vivo Antimalarial Efficacies of Optimized Tetracyclines , 2013, Antimicrobial Agents and Chemotherapy.

[27]  David S. Roos,et al.  A plastid organelle as a drug target in apicomplexan parasites , 1997, Nature.

[28]  C. Wongsrichanalai,et al.  Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance. , 2013, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[29]  S. Briolant,et al.  Plasmodium falciparum proteome changes in response to doxycycline treatment , 2010, Malaria Journal.