The failure to treat everyday bacterial infections is a current threat as pathogens are finding new ways to thwart antibiotics through mechanisms of resistance and intracellular refuge, thus rendering current antibiotic strategies ineffective. Cellpenetrating peptides (CPPs) are providing a means to improve antibiotics that are already approved for use. Through coadministration and conjugation of antibiotics with CPPs, improved accumulation and selectivity with alternative and/or additional modes of action against infections have been observed. Herein, we review the recent progress of this antibiotic-cell-penetrating peptide strategy in combatting sensitive and drug-resistant pathogens. We take a closer look into the specific antibiotics that have been enhanced, and in some cases repurposed as broad-spectrum drugs.Through the addition and conjugation of cell-penetrating peptides to antibiotics, increased permeation across mammalian and/or bacterial membranes and a broader range in bacterial selectivity have been achieved.
Intracellular
pathogens can thrive within mammalian cells and are
inaccessible to many antimicrobial agents. Herein, we present a facile
method of enhancing the cell penetrating and antibacterial properties
of cationic amphiphilic polyproline helices (CAPHs) with modifications
to the hydrophobic moiety at the N-terminus. These altered CAPHs display
superior cell penetration within macrophage cells, and in some cases,
minimal cytotoxicity. Furthermore, one CAPH, Pentyl-P14 exhibited excellent antibacterial activity against multiple strains
of pathogenic bacteria and promoted the clearance of intracellular Shigella within macrophages.
Synthesis of (E)-1-(3-methylbutylidene)-2-ethylene-cyclohexane (14). LDA (50 mL; 1.5 M in THF; 75 mmol) was dissolved in THF (150 mL) and cooled to -78 °C. Cyclohexanone (7.8 mL; 75 mmol) was added dropwise over 5 minutes and stirred for 25 minutes at -78 °C. Isovaleraldehyde (8.11 mL; 74 mmol) was added over 5 minutes and the mixture was stirred for an additional 20 minutes at -78 °C. The reaction mixture was quenched with saturated NH 4 Cl (125 mL). The solution was allowed to warm to room temperature, transferred to a 1000-mL separatory funnel with EtOAc (250 mL) and extracted with additional EtOAc (250 mL). Combined organic layers were washed with brine (200 mL), and dried with Na 2 SO 4 . The solvent was removed on a rotary evaporator and purified by flash chromatography (silica gel, hexanesEtOAc (400 mL), 10% (800 mL), to give the aldol addition product 2-(1-hydroxy-3-methylbutyl)cyclohexanone as a mixture of diastereomers (11.068 g; 81% yield). CeCl 3 •7H 2 O (72 g; 192 mmol) and NaI (29 g; 192 mmol) were dissolved in CH 3 CN (750 mL) and 2-(1-hydroxy-3-methylbutyl)cyclohexanone (11.0 g, 59.7 mmol) was added, gently refluxed for 2 d, quenched with aqueous HCl (1.0 M; 300 mL), and extracted with Et 2 O (2 x 300 mL). The combined organic layers were washed with water (300 mL), saturated aqueous NaHCO 3 (300 mL), brine (150 mL), dried with Na 2 SO 4 and the crude product was purified by flash chromatography (silica gel, 10% EtOAc/hexanes) to give (2E)-2-(3-methylbutylidene)cyclohexanone (5.377 g; 54% yield). A suspension of methyltriphenylphosphonium bromide (10.2 g; 28.6 mmol) in THF (90 mL) was cooled to -78 °C, and nBuLi in THF (18 mL; 1.6 M; 29 mmol) was added, and the mixture was allowed warm to room temperature. The reaction mixture was then cooled to -78 °C and (2E)-2-(3-methylbutylidene)cyclohexanone (4.834 g; 29.1 mmol) in THF was added via addition funnel over 45 minutes. The reaction mixture was allowed to warm for 30 minutes, diluted with water (100 mL), separated, and extracted with hexanes (2 x 20 mL). The combined organic extracts were washed with water (3 x 100mL), dried with Na 2 SO 4 , the solvent was removed by the rotary evaporator, and the crude product was purified by flash chromatography (silica gel, petroleum ether) to give 14. Colorless oil; yield: 3.868 g (35% based on three steps).
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