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Pentobra: A Potent Antibiotic with Multiple Layers of Selective Antimicrobial Mechanisms against Propionibacterium Acnes.

Schmidt NW, Agak GW, Deshayes S, Yu Y, Blacker A, Champer J, Xian W, Kasko AM, Kim J, Wong GC - J. Invest. Dermatol. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Bioengineering, University of California, Los Angeles, California, USA [2] Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.

ABSTRACT
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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Related in: MedlinePlus

Pentobra is bactericidal against Propionibacterium acnes(A) Structure of Pentobra. (B)P. acnes ATCC 6919 was incubated with different concentrations of Pentobra, tobramycin, or pen peptide (0–52 μM) for 3 hours and tested for bactericidal activity using the CFU assay. Data show average CFU from three independent experiments (n = 3), error bars are ± SEM.
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Figure 1: Pentobra is bactericidal against Propionibacterium acnes(A) Structure of Pentobra. (B)P. acnes ATCC 6919 was incubated with different concentrations of Pentobra, tobramycin, or pen peptide (0–52 μM) for 3 hours and tested for bactericidal activity using the CFU assay. Data show average CFU from three independent experiments (n = 3), error bars are ± SEM.

Mentions: Here we report an aminoglycoside-based compound with bactericidal activity against P. acnes. Our design is informed by recent work which elucidate the roles of cationic and hydrophobic residues in AMP sequences (Schmidt et al., 2011; Schmidt et al., 2012b), Cell-penetrating peptide (CPP) sequences (Mishra et al., 2011), and non-peptidic AMP mimetic compositions (Hu et al., 2013; Schmidt et al., 2012a), and relate them to the geometric requirements of membrane permeabilization. Tobramycin, a potent aminoglycoside, is conjugated to a short 12AA peptide to equip the composite molecule, Pentobra (Figure 1A), with preferential activity against bacterial membranes like an AMP, so that the composite molecule has multiple levels of selectivity and multiple mechanisms of killing (Schmidt et al., 2014). The work presented herein, demonstrates that equipping aminoglycosides with selective membrane activity is a viable approach for developing antibiotics against P. acnes that are effective in cutaneous environments.


Pentobra: A Potent Antibiotic with Multiple Layers of Selective Antimicrobial Mechanisms against Propionibacterium Acnes.

Schmidt NW, Agak GW, Deshayes S, Yu Y, Blacker A, Champer J, Xian W, Kasko AM, Kim J, Wong GC - J. Invest. Dermatol. (2015)

Pentobra is bactericidal against Propionibacterium acnes(A) Structure of Pentobra. (B)P. acnes ATCC 6919 was incubated with different concentrations of Pentobra, tobramycin, or pen peptide (0–52 μM) for 3 hours and tested for bactericidal activity using the CFU assay. Data show average CFU from three independent experiments (n = 3), error bars are ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430421&req=5

Figure 1: Pentobra is bactericidal against Propionibacterium acnes(A) Structure of Pentobra. (B)P. acnes ATCC 6919 was incubated with different concentrations of Pentobra, tobramycin, or pen peptide (0–52 μM) for 3 hours and tested for bactericidal activity using the CFU assay. Data show average CFU from three independent experiments (n = 3), error bars are ± SEM.
Mentions: Here we report an aminoglycoside-based compound with bactericidal activity against P. acnes. Our design is informed by recent work which elucidate the roles of cationic and hydrophobic residues in AMP sequences (Schmidt et al., 2011; Schmidt et al., 2012b), Cell-penetrating peptide (CPP) sequences (Mishra et al., 2011), and non-peptidic AMP mimetic compositions (Hu et al., 2013; Schmidt et al., 2012a), and relate them to the geometric requirements of membrane permeabilization. Tobramycin, a potent aminoglycoside, is conjugated to a short 12AA peptide to equip the composite molecule, Pentobra (Figure 1A), with preferential activity against bacterial membranes like an AMP, so that the composite molecule has multiple levels of selectivity and multiple mechanisms of killing (Schmidt et al., 2014). The work presented herein, demonstrates that equipping aminoglycosides with selective membrane activity is a viable approach for developing antibiotics against P. acnes that are effective in cutaneous environments.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Bioengineering, University of California, Los Angeles, California, USA [2] Department of Chemistry and Biochemistry, University of California, Los Angeles, California, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus