Antibiotic Drugs Aminoglycosides Cleave DNA at Abasic Sites: Shedding New Light on Their Toxicity?

Abstract

Abasic sites are probably the most common lesions in DNA resulting from the hydrolytic cleavage of glycosidic bonds that can occur spontaneously and through DNA alkylation by anticancer agents, by radiotherapy, and during the repair processes of damaged nucleic bases. If not repaired, the abasic site can be mutagenic or lethal. Thus, compounds able to specifically bind and react at abasic sites have attracted much attention for therapeutic and diagnostic purposes. Here, we report on the efficient cleavage activity of characteristic antibiotic drugs of the major aminoglycosides (AG) family at abasic sites introduced either by depurination in a plasmidic DNA or site specifically in a synthetic oligonucleotide. Among the antibiotic AG drugs selected for this study, neomycin B is the most efficient (a 0.1 μM concentration induces 50% cleavage of an abasic site containing DNA). This cleavage activity could be related to aminoglycoside toxicity but also find medicinal applications through potentiation of cancer radiotherapy and chemotherapy with alkylating drugs. In the search for antibiotic and antiviral agents, we have previously described the synthesis of derivatives of the small aminoglycoside neamine, which corresponds to rings I and II of neomycin B constituted of four rings. The cleavage activity at abasic sites of four of these neamine derivatives is also reported in the present study. One of them appeared to be much more active than the parent compound neamine with cleavage efficiency close to that of neomycin.

Interaction of Functionalized Naphthalenophanes with Abasic Sites in DNA: DNA Cleavage, DNA Cleavage Inhibition, and Formation of Ligand–DNA Adducts

“…However, in parallel to inhibiting APE1 activity, polyazacyclophane ligands also induce an enzyme‐independent cleavage of AP sites through a β‐elimination mechanism, due to the presence of secondary amino groups in the ligand structure (Scheme , bottom) . The latter process, reminiscent of the action of AP lyases (class I endonucleases), was also observed for oligopeptides KWK and KWKK, as well as several other small‐molecule ligands endowed with primary or secondary amino groups, eponymously termed “artificial AP lyases” . It has been proposed that such molecules may interfere with the normal BER process because of the accumulation of “dirty ends” (products of β‐ and β,δ‐elimination) that cannot be utilized as substrates by DNA polymerases, and therefore, also increase the cytotoxic effect of DNA‐alkylating drugs …”

“…[23,25] The latter process, reminiscent of the action of AP lyases (class Ie ndonucleases), was also observed for oligopeptides KWK and KWKK, [27][28][29] as well as several other small-molecule ligands endowed with primary or secondary amino groups,e ponymously termed "artificial AP lyases". [17,[30][31][32][33][34] It has been proposed that such molecules may interfere with the normal BER process because of the accumulation of "dirty ends" (products of b-a nd b,d-elimination) that cannotb eu tilized as substrates by DNA polymerases,a nd therefore, also increase the cytotoxic effect of DNA-alkylating drugs. [35,36] To fully understand the action of ligandst argeting AP sites in biological systems, it would be preferable to decouple the two aforementioned effects, namely,t he inhibition of APE1-induced hydrolysis and the ligand-promoted cleavage of AP sites.…”

Selective condensation of DNA by aminoglycoside antibiotics

“…Furthermore, double-stranded DNA can be effectively converted from the B-DNA to the A-DNA conformation by this drug (Robinson and Wang 1996 ). Neomycin was indicated as the most efficient aminoglycoside in cleaving DNA strands at basic sites (Perigolo De Oliveira et al 2013 ). As mentioned above, kanamycin also has cleaving activity, however weaker than that of neomycin.…”

Amphiphilic Aminoglycosides as Medicinal Agents

“…Compounds able to specifically bind and react at abasic sites have attracted much attention for therapeutic and diagnostic purposes. We studied the efficient cleavage activity of AG antibiotic drugs and of some AAGs at abasic sites, introduced either by depurination in a plasmidic DNA or site-specifically in a synthetic oligonucleotide [157]. NEO was found to be the most efficient cleaving AG drug, followed by the AAG 76 (Figure 18) resulting from the conjugation of the NEA core to the nucleic base adenine (EC 50 = 0.09 and 0.15 µM, respectively, and EC 50 (NEA) = 0.9 µM).…”

“…Figure18. Structure of the most efficient DNA-cleaving AAG identified, 76, at abasic sites[157], and of the amphiphilic azobenzene-NEO conjugate 77 forming nanostructures[158].…”