Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol

Abstract

Chloramphenicol (CAM) is a broad-spectrum antibiotic, limited to occasional only use in developed countries because of its potential toxicity. To explore the influence of polyamines on the uptake and activity of CAM into cells, a series of polyamine–CAM conjugates were synthesized. Both polyamine architecture and the position of CAM-scaffold substitution were crucial in augmenting the antibacterial and anticancer potency of the synthesized conjugates. Compounds 4 and 5, prepared by replacement of dichloro-acetyl group of CAM with succinic acid attached to N4 and N1 positions of N8,N8-dibenzylspermidine, respectively, exhibited higher activity than CAM in inhibiting the puromycin reaction in a bacterial cell-free system. Kinetic and footprinting analysis revealed that whereas the CAM-scaffold preserved its role in competing with the binding of aminoacyl-tRNA 3′-terminus to ribosomal A-site, the polyamine-tail could interfere with the rotatory motion of aminoacyl-tRNA 3′-terminus toward the P-site. Compared to CAM, compounds 4 and 5 exhibited comparable or improved antibacterial activity, particularly against CAM-resistant strains. Compound 4 also possessed enhanced toxicity against human cancer cells, and lower toxicity against healthy human cells. Thus, the designed conjugates proved to be suitable tools in investigating the ribosomal catalytic center plasticity and some of them exhibited greater efficacy than CAM itself.

Molecular dynamics simulations suggest why the A2058G mutation in 23S RNA results in bacterial resistance against clindamycin

“…1). This observation is in accord with two conformers of clindamycin observed in crystal structures [21–23] and docking studies [25], suggesting that there is room for clindamycin to rotate its pyrrolidynyl propyl group even once bound in the ribosome. …”

3-Amino-4-aminoximidofurazan derivatives: small molecules possessing antimicrobial and antibiofilm activity againstStaphylococcus aureusandPseudomonas aeruginosa

“…The presence of polyamine based skeleton in our molecules can attribute to the disruption of biofilm (Kostopoulou et al . ). The reaction of 3‐amino‐4‐aminoximidofurazan with the substituted nitriles yielded a small library of compounds with polyamine skeleton.…”

“…Another report also revealed that polyamine conjugated chloramphenicol showed higher antimicrobial property than the unconjugated chloramphenicol (Kostopoulou et al . ). So, we hypothesized that the polyamine based new synthetic molecules could be efficient antimicrobials.…”

The antibiotic chloramphenicol may be an effective new agent for inhibiting the growth of multiple myeloma

“…As the structure of mammalian mitochondria is similar to prokaryotes [13, 14, 20], mitochondrial protein synthesis can also be inhibited by chloramphenicol. Our results indicate that chloramphenicol sharply suppresses ATP levels in human MM cell lines and primary MM cells at concentrations ≥ 25 μg/mL and significantly inhibits tumor growth at concentrations ≥ 50 μg/mL.…”

“…Prior reports showed that chloramphenicol inhibits mammalian mitochondrial protein synthesis and causes mitochondrial stress, leading to decreased ATP biosynthesis [9–14]. The use of chloramphenicol as an antimicrobial agent to treat bacterial infections has decreased over the years because it suppresses bone marrow function in humans secondary to inhibition of mitochondrial protein synthesis [15, 16].…”