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.

Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.

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Chloramphenicol (CAM) inhibits peptide bond formation by binding to the 50S subunit of prokaryotic ribosomes and interfering competitively with the binding of the aminoacyl-tRNA 3'-terminus to ribosomal A-site. Further studies have demonstrated that CAM (I) reacts rapidly with a model initiator ribosomal complex [poly(U)-programmed ribosomes from Escherichia coli, bearing AcPhe-tRNA at the P-site], complex C, to form an encounter complex CI which is then isomerized slowly to a tighter complex, C I. Herein, we show by time-resolved footprinting analysis that CAM produces a footprint in CI complex, comprising nucleotides A2451, G2505, and U2506, all exhibiting reduced reactivity against base-specific modifying agents. When C I complex is footprinted, the reactivities of G2505 and U2506 are almost restored, while protection is observed at A2062 and altered reactivity at A2058 and A2059. Our results suggest that CAM initially binds to a hydrophobic crevice composed of nucleotides located adjacently to the A-site (CI complex). Soon after, CAM shifts slowly to a final position, in which the interaction between the p-nitrobenzyl group of CAM and the base of A2451 is conserved, while the dichloroacetyl group reorientates toward A2062. Analogous behavior is observed, if CAM is modified by replacement of dichloroacetyl group with-alanyl. However, insertion at this position of a bulkier group, such as phenylalanyl-phenylalanyl group, sterically prevents CAM accommodation to its initial binding site and favors its direct fitting into the final binding pocket. Our data correlate well with recent crystallographic results regarding CAM binding on Thermus thermophilus and E. coli ribosomes.

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Pegylated DOX-C60 conjugates (1:1) and (2:1) with well-defined structure were successfully synthesized and found to exhibit comparable, but with a delayed onset, antiproliferative activity with free DOX against MCF-7 cancer cells. The results obtained justify further investigation of the potential of these conjugates as anticancer nanomedicines.

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