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Pentobra: A Potent Antibiotic with Multiple Layers of Selective Antimicrobial
Mechanisms against Propionibacterium Acnes
#MMPMID25668237
Schmidt NW
; Agak GW
; Deshayes S
; Yu Y
; Blacker A
; Champer J
; Xian W
; Kasko AM
; Kim J
; Wong GCL
J Invest Dermatol
2015[Jun]; 135
(6
): 1581-1589
PMID25668237
show ga
Although antibiotics are a common treatment for acne, the difficulties inherent
to effective antimicrobial penetration in sebum and selective antimicrobial
action in the skin are compounded by increasing resistance of Propionibacterium
acnes clinical isolates. To address these problems, we engineered Pentobra, a
peptide-aminoglycoside molecule that has multiple mechanisms of antibacterial
action and investigated whether it can be a potential candidate for the treatment
of acne. Pentobra combines the potent ribosomal activity of aminoglycosides with
the bacteria-selective membrane-permeabilizing abilities of antimicrobial
peptides. Pentobra demonstrated potent and selective killing of P. acnes but not
against human skin cells in vitro. In direct comparison, Pentobra demonstrated
bactericidal activity and drastically outperformed free tobramycin (by 5-7 logs)
against multiple P. acnes clinical strains. Moreover, electron microscopic
studies showed that Pentobra had robust membrane activity, as treatment with
Pentobra killed P. acnes cells and caused leakage of intracellular contents.
Pentobra may also have potential anti-inflammatory effects as demonstrated by
suppression of some P. acnes-induced chemokines. Importantly, the killing
activity was maintained in sebaceous environments as Pentobra was bactericidal
against clinical isolates in comedones extracts isolated from human donors. Our
work demonstrates that equipping aminoglycosides with selective membrane activity
is a viable approach for developing antibiotics against P. acnes that are
effective in cutaneous environments.
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