Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria

Abstract 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. Cell‐penetrating 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.