title: In vitro and in vivo activity of solithromycin (CEM-101) against Plasmodium species.
abstract: With the emergence of Plasmodium falciparum infections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potent in vitro activity against the NF54 strain of P. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In an in vivo model of P. berghei infection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promising in vitro and in vivo data support further investigations into the development of solithromycin as an antimalarial agent.
authors.affiliation: Swiss Tropical & Public Health Institute, CH-4002 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Eric
authors.initials: E
authors.lastname: Ekland
authors.forename: J Carl
authors.initials: JC
authors.lastname: Craft
authors.forename: Julie
authors.initials: J
authors.lastname: Lotharius
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Prabhavathi
authors.initials: P
authors.lastname: Fernandes
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D006801:Humans; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D018942:Macrolides; D014230:Triazoles; C547755:solithromycin
references.citation: Antimicrob Agents Chemother. 1979 Dec;16(6):710-8
references.pmid: 394674
references.citation: FASEB J. 2011 Oct;25(10):3583-93
references.pmid: 21746861
references.citation: PLoS Biol. 2011 Aug;9(8):e1001138
references.pmid: 21912516
references.citation: N Engl J Med. 2009 Jul 30;361(5):455-67
references.pmid: 19641202
references.citation: Mol Biochem Parasitol. 2004 Sep;137(1):23-33
references.pmid: 15279948
references.citation: Antimicrob Agents Chemother. 2011 May;55(5):1997-2003
references.pmid: 21282444
references.citation: Trends Parasitol. 2009 Dec;25(12):540-4
references.pmid: 19819757
references.citation: Parassitologia. 1999 Sep;41(1-3):301-8
references.pmid: 10697872
references.citation: J Biol Chem. 2007 Jan 26;282(4):2494-504
references.pmid: 17110371
references.citation: Antimicrob Agents Chemother. 2010 Dec;54(12):4961-70
references.pmid: 20855725
references.citation: N Engl J Med. 2008 Dec 11;359(24):2619-20
references.pmid: 19064625
references.citation: Antimicrob Agents Chemother. 1997 Mar;41(3):677-86
references.pmid: 9056013
references.citation: Biochem Soc Trans. 2010 Jun;38(3):775-82
references.pmid: 20491664
references.citation: N Engl J Med. 2009 Jul 30;361(5):540-1
references.pmid: 19641219
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4400-5
references.pmid: 21300861
references.citation: Int J Parasitol. 1995 Apr;25(4):531-2
references.pmid: 7635629
references.citation: Clin Infect Dis. 2006 Nov 15;43(10):1264-71
references.pmid: 17051490
references.citation: Antimicrob Agents Chemother. 2010 Jan;54(1):230-8
references.pmid: 19884376
references.citation: Antimicrob Agents Chemother. 2009 Sep;53(9):3734-43
references.pmid: 19564365
references.citation: Curr Opin Infect Dis. 2011 Dec;24(6):570-7
references.pmid: 22001944
references.citation: Antimicrob Agents Chemother. 2010 Dec;54(12):5399-402
references.pmid: 20855733
references.citation: Antimicrob Agents Chemother. 2007 Oct;51(10):3485-90
references.pmid: 17698630
references.citation: Int J Antimicrob Agents. 2011 Jan;37(1):39-45
references.pmid: 21075602
references.citation: Curr Opin Microbiol. 2007 Aug;10(4):363-70
references.pmid: 17709280
references.citation: Acta Trop. 1993 Jan;52(4):313-6
references.pmid: 8094593
references.citation: Lancet. 2011 Oct 8;378(9799):1316-23
references.pmid: 21903251
references.citation: Antimicrob Agents Chemother. 2002 Aug;46(8):2315-20
references.pmid: 12121898
references.citation: Int J Antimicrob Agents. 2010 Jun;35(6):537-43
references.pmid: 20211548
references.citation: Nat Rev Microbiol. 2009 Dec;7(12):864-74
references.pmid: 19881520