Identification of 5,6-dihydroimidazo[2,1-b]thiazoles as a new class of antimicrobial agents.
In an effort to develop novel antimicrobial agents against drug-resistant bacterial infections, 5,6-dihydroimidazo[2,1-b]thiazole compounds were synthesized and tested for their antimicrobial activity. Eight compounds comprised by two sub-scaffolds were identified as hits against methicillin-resistant Staphylococcus aureus (MRSA). These hits were modified at 6-position by replacing (S)-6 to (R)-6 configuration and the (R)-isomers increased their antimicrobial activities by two-fold. The most active compound showed a MIC90value of 3.7μg/mL against MRSA in a standard microdilution bacterial growth inhibitory assay. This compound protected wax moth worms against MRSA at a dose of 5× MIC using a worm infectious model. This compound also exhibited inhibition of DNA gyrase activity in a DNA gyrase supercoil assay, suggesting the 5,6-dihydroimidazo[2,1-b]thiazoles may target DNA gyrase for the antimicrobial action.
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States. Electronic address: yli@tpims.org.
Yangmei
Y
Li
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States.
Nina
N
Bionda
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, United States.
Renee
R
Fleeman
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States.
Hongjie
H
Wang
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States.
Akihiko
A
Ozawa
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States.
Richard A
RA
Houghten
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, United States.
Lindsey
L
Shaw
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D027081:DNA Gyrase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009036:Moths / Q000187:drug effects* / Q000382:microbiology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D007093:Imidazoles; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase
Antimicrobial; DNA gyrase; Heterocyclic; Imidazothiazole; MRSA
Clin Microbiol Infect. 2006 Mar;12 Suppl 1:16-23
16445720
J Clin Microbiol. 2003 Jan;41(1):5-14
12517819
Antimicrob Agents Chemother. 2013 Jan;57(1):26-36
23027196
J Antimicrob Chemother. 2005 Sep;56(3):470-80
16040625
Crit Rev Biochem Mol Biol. 1991;26(3-4):335-75
1657531
Adv Appl Microbiol. 2012;78:25-53
22305092
JAMA. 2007 Oct 17;298(15):1763-71
17940231
FEMS Immunol Med Microbiol. 2002 Oct 11;34(2):153-7
12381467
Clin Infect Dis. 2003 Jan 15;36(2):159-68
12522747
Clin Infect Dis. 2007 Sep 15;45 Suppl 3:S184-90
17712745
Antimicrob Agents Chemother. 2006 Apr;50(4):1228-37
16569833
Int J Biomed Sci. 2006 Jun;2(2):85-100
23674971
J Med Chem. 2008 Sep 11;51(17):5243-63
18690678
Infection. 2008 Feb;36(1):85-7
18165857
Appl Microbiol Biotechnol. 2011 Nov;92(3):479-97
21904817
J Infect Dis. 2005 Jun 15;191(12):2149-52
15898002
Antimicrob Agents Chemother. 2002 Aug;46(8):2595-601
12121938
Curr Med Chem. 2006;13(1):1-23
16457636
Ann N Y Acad Sci. 2013 Jan;1277:139-58
23215859