Illicit uptake of peptide-based antibiotics through bacterial peptide transporters: an approach towards overcoming drug resistance

Illicit transport pertains to the unauthorized entry of molecules into cells through transporters that are initially intended for other physiological substances. Recently, it has been demonstrated that the peptide-based antibiotic negamycin can permeate the cytosolic membrane of Escherichia coli via dipeptide (EcDpp), sensitivity to antimicrobial peptide (EcSap), and oligopeptide (EcOpp) transporters. However, no example of such an illicit transport mechanism for the Haemophilus influenzae Sap (HiSap) transporter has been reported. So, an in-depth in silico study was performed to identify new peptide-based antibiotics showing binding affinities for the substrate-binding proteins EcDppA, EcSapA, and HiSapA. The results indicated that the three target proteins share sequence and structural similarities among them. Moreover, a virtual screening of 230 peptide-based antibiotics against these proteins identified eight compounds with higher binding affinities. Among these, three compounds (1, 6, and 129) demonstrate superior absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as drug-like characteristics. Comprehensive molecular dynamics (MD) simulation hints towards the conformational stability and favourable binding energy of these compounds with EcDppA, EcSapA, and HiSapA. The probability density function (PDF) and dynamic cross-correlation map (DCCM) underscored the significance of the binding-site loop in ligand dynamics and major domain movements, respectively. In conclusion, the results from this study propose that Compounds 1, 6, and 129 could function as effective broad-spectrum antibiotics against Gram-negative pathogens and can also act as a template for designing more such peptide-based antibiotics for illicit transport across various other pathogens.