Rationally designed short cationic α-helical peptides with selective anticancer activity

Hypothesis Naturally derived or synthetic anticancer peptides (ACPs) have emerged as a new generation of anticancer agents with higher selectivity for cancer cells and less propensity for drug resistance. Despite the structural diversity of ACPs, α-helix is the most common secondary structure among them. Herein we report the development of a new library of short cationic amphiphilic α-helical ACPs with selective cytotoxicity against colorectal and cervical cancer. Experiments The peptides had a general formula C(XXYY)3 with C representing amino acid cysteine (providing a -SH group for molecular conjugation), X representing hydrophobic amino acids (isoleucine (I) or leucine (L)), and Y representing cationic amino acids (arginine (R) or lysine (K)). Two variants of the peptides were synthesized by adding additional Isoleucine residues to the C-terminal and replacing the N-terminal cysteine with LC-propargylglycine (LC-G) to investigate the effect of N-terminal and C-terminal variation on the anticancer activity. The structure and physicochemical properties of the peptides were determined by RP-HPLC, LC-MS and CD spectroscopy. The cytotoxicity of the peptides in different cell lines was assessed by MTT test, cell proliferation assay and mitochondrial damage assay. The mechanism of cell selectivity of the peptides was investigated by studying their interfacial behaviour at the air/water and lipid/water interface using Langmuir trough. Findings The peptides consisting of K residues in their hydrophilic domains exhibited more selective anticancer activity whereas the peptides containing R exhibited strong toxicity in normal cells. The anticancer activity of the peptides was a function of their helical content and their hydrophobicity. Therefore, the addition of two I residues at C-terminal enhanced the anticancer activity of the peptides by increasing their hydrophobicity and their helical content. These two variants also exhibited strong anticancer activity against colorectal cancer multicellular tumour spheroids (MCTS). The higher toxicity of the peptides in cancer cells compared to normal cells was the result of higher penetration into the negatively charged cancer cell membranes, leading to higher cellular uptake, and their cytotoxic effect was mainly exerted by damaging the mitochondrial membranes leading to apoptosis. The results from this study provide a basis for rational design of new α-helical ACPs with enhanced anticancer activity and selectivity

The role of beta-lactamase-producing-bacteria in mixed infections

Beta-lactamase-producing bacteria (BLPB) can play an important role in polymicrobial infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme beta-lactamase. BLPB may not only survive penicillin therapy but can also, as was demonstrated in in vitro and in vivo studies, protect other penicillin-susceptible bacteria from penicillin by releasing the free enzyme into their environment. This phenomenon occurs in upper respiratory tract, skin, soft tissue, surgical and other infections. The clinical, in vitro, and in vivo evidence supporting the role of these organisms in the increased failure rate of penicillin in eradication of these infections and the implication of that increased rate on the management of infections is discussed