Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae.
We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen.
Pharmaceutical Design and Discovery Research Group, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki (UHEL), Helsinki, Finland.
Leena
L
Hanski
Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
Dominik
D
Ausbacher
Pharmaceutical Design and Discovery Research Group, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki (UHEL), Helsinki, Finland.
Terttu M
TM
Tiirola
Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
Morten B
MB
Strøm
Pharmaceutical Design and Discovery Research Group, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki (UHEL), Helsinki, Finland.
Pia M
PM
Vuorela
D000597:Amino Acids, Branched-Chain / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D023521:Chlamydophila Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016993:Chlamydophila pneumoniae / Q000166:cytology / Q000254:growth & development* / Q000472:pathogenicity; D006801:Humans
D000597:Amino Acids, Branched-Chain