Inhibitory effect of the natural product betulin and its derivatives against the intracellular bacterium Chlamydia pneumoniae.
Chlamydia pneumoniae is a universal pathogen that has been indicated to play a part in the development of asthma, atherosclerosis and lung cancer. The complete eradication of this intracellular bacterium is in practice impossible with the antibiotics that are currently in use and studies on new antichlamydial compounds is challenging because Chlamydia research lacks the tools required for the genetic modification of this bacterium. Betulin is a natural lupane-class triterpene derived from plants with a wide variety of biological activities. This compound group thus has wide medical potentials, and in fact has been shown to be active against intracellular pathogens. For this reason, betulin and its derivatives were selected to be assayed against C. pneumoniae in the present study. Thirty-two betulin derivatives were assayed against C. pneumoniae using an acute infection model in vitro. Five promising compounds with potential lead compound characteristics were identified. Compound 24 (betulin dioxime) gave a minimal inhibitory concentration (MIC) of 1 microM against strain CWL-029 and showed activity in nanomolar concentrations, as 50% inhibition was achieved at 290 nM. The antichlamydial effect of 24 was confirmed with a clinical isolate CV-6, showing a MIC of 2.2 microM. Previous research on betulin and its derivatives has not identified such a remarkable inhibition of Gram-negative bacterial growth. Furthermore, we also demonstrated that this antichlamydial activity was not due to PLA(2) (EC 3.1.1.4) inhibition caused by the betulin derivatives.
Salin
Olli
O
Pharmaceutical Sciences, Department of Biosciences, Abo Akademi University, BioCity, Artillerigatan 6 A, FI-20520 Turku, Finland. olli-pekka.salin@abo.fi
Alakurtti
Sami
S
Pohjala
Leena
L
Siiskonen
Antti
A
Maass
Viola
V
Maass
Matthias
M
Yli-Kauhaluoma
Jari
J
Vuorela
Pia
P
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D006151:Guanosine / Q000096:biosynthesis; D006801:Humans; D008826:Microbial Sensitivity Tests; D054467:Phospholipases A2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
D000900:Anti-Bacterial Agents; D006151:Guanosine; D054467:Phospholipases A2; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid