Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems

Gootz, Thomas D.; Barrett, John; Sutcliffe, Joyce A.

doi:10.1128/aac.34.1.8

Cited by 92 publications

(56 citation statements)

References 45 publications

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“…Rifampin is the key component of the standard multidrug regimen used for treatment of leprosy, and it has been shown that PCR-based DNA sequence analysis of the rpoB gene of M. leprae was in full concordance with rifampin susceptibility testing in the mouse footpad system (17,30). In addition to dapsone and rifampin, ofloxacin is also used for leprosy treatment and is a quinolone with an action mechanism based on interaction with DNA gyrase (2); SNPs in gyrA and gyrB confer resistance or hypersensitivity to quinolones (15). Although there is not yet an official definition of multidrug resistance (MDR) in leprosy, in parallel with tuberculosis, we adopt this terminology when we encounter resistance to rifampin and one other drug of the standard MDT regimen.…”

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confidence: 99%

Drug and Multidrug Resistance among Mycobacterium leprae Isolates from Brazilian Relapsed Leprosy Patients

et al. 2012

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h Skin biopsy samples from 145 relapse leprosy cases and from five different regions in Brazil were submitted for sequence analysis of part of the genes associated with Mycobacterium leprae drug resistance. Single nucleotide polymorphisms (SNPs) in these genes were observed in M. leprae from 4 out of 92 cases with positive amplification (4.3%) and included a case with a mutation in rpoB only, another sample with SNPs in both folP1 and rpoB, and two cases showing mutations in folP1, rpoB, and gyrA, suggesting the existence of multidrug resistance (MDR). The nature of the mutations was as reported in earlier studies, being CCC to CGC in codon 55 in folP (Pro to Arg), while in the case of rpoB, all mutations occurred at codon 531, with two being a transition of TCG to ATG (Ser to Met), one TCG to TTC (Ser to Phe), and one TCG to TTG (Ser to Leu). The two cases with mutations in gyrA changed from GCA to GTA (Ala to Val) in codon 91. The median time from cure to relapse diagnosis was 9.45 years but was significantly shorter in patients with mutations (3.26 years; P ‫؍‬ 0.0038). More than 70% of the relapses were multibacillary, including three of the mutation-carrying cases; one MDR relapse patient was paucibacillary. There is no doubt about the efficiency of the currently used multidrug therapy (MDT) scheme for treatment of leprosy, as demonstrated by the strong decrease in disease prevalence since its implementation and the low number of reported relapse cases (18). However, there has been a scarcity of in-depth studies of relapse occurrences in recent decades (27). As is known, differentiating diagnosis of relapse and reactional states poses some difficulties in the field, being responsible for under-or overdiagnosis of both disease stages. This is important because undiagnosed relapse cases could contribute to continuing disease transmission. In addition, hardly any data on the contribution of emergence of drug-resistant strains of Mycobacterium leprae to leprosy relapses exist.Diaminodiphenylsulfone (DDS), also called dapsone, was the first drug to be effective against leprosy worldwide, and the first cases of resistance to dapsone were detected in 1964 and involved two single nucleotide polymorphisms (SNPs) in the gene folP1, located in codons 53 and 55 (8, 9, 14, 29). Rifampin is the key component of the standard multidrug regimen used for treatment of leprosy, and it has been shown that PCR-based DNA sequence analysis of the rpoB gene of M. leprae was in full concordance with rifampin susceptibility testing in the mouse footpad system (17, 30). In addition to dapsone and rifampin, ofloxacin is also used for leprosy treatment and is a quinolone with an action mechanism based on interaction with DNA gyrase (2); SNPs in gyrA and gyrB confer resistance or hypersensitivity to quinolones (15). Although there is not yet an official definition of multidrug resistance (MDR) in leprosy, in parallel with tuberculosis, we adopt this terminology when we encounter resistance to rifampin and one other drug of the standard M...

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Drug and Multidrug Resistance among Mycobacterium leprae Isolates from Brazilian Relapsed Leprosy Patients

et al. 2012

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“…The effects of drugs were examined over a concentration range of 0 to 500 pM. (13). Even ciprofloxacin, the most active oral antimicrobial agent in clinical use (14,43), shows only low activity against calf thymus topoisomerase II.…”

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Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

Elsea

McGuirk

Gootz

et al. 1993

Antimicrob Agents Chemother

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). However, the features of the drug that contribute to its activity towards mammalian systems have not been characterized. Therefore, CP-115,953 and a series of related quinolones were examined for their activity against calf thymus topoisomerase H and cultured mammalian cells. CP-115,953 stimulated DNA cleavage mediated by the type H enzyme with a potency that was -600-fold greater than that of the antimicrobial quinolone ciprofloxacin and -50-fold greater than that of the antineoplastic drug etoposide. As determined by the ability to enhance enzyme-mediated DNA cleavage, quinolone activity towards calf thymus topoisomerase H was enhanced by the presence of a cyclopropyl group at the N-1 ring position and by the presence of a fluorine at C-8. Furthermore, the 4'-hydroxyphenyl substituent at the C-7 position was critical for the potency of CP-115,953 towards the mammalian type H enzyme. In this regard, the aromatic nature of the C-7 ring as well as the presence and the position of the 4'-hydroxyl group contributed greatly to drug activity. Finally, the cytotoxicity of quinolones in the CP-115,953 series towards mammalian cells paralleled the in vitro stimulation of DNA cleavage by topoisomerase H rather than the inhibition of enzyme-catalyzed DNA relaxation. This correlation strongly suggests that these quinolones promote cell death by converting topoisomerase IT to a cellular poison.

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“…Although the biological activity of these two compounds reflects a high degree of selectivity for DNA gyrase, their potency against topoisomerase II provides additional evidence that common structural themes may emerge for inhibitors that induce DNA breakage by both classes of enzymes. As pointed out previously (1,2,12,13), such data also suggest the need to investigate the potential toxicity of compounds developed as antibacterial agents against bacterial DNA gyrase which might result from their interaction with human topoisomerase II. This issue has been raised regarding ciprofloxacin (1, 2, 12, 13), which has DNA breakage activity when tested at high concentrations with purified topoisomerase 11 (1,12) and was recently found to induce double-strand breaks in human lymphoblastoid cells (2).…”

Section: Discussionmentioning

confidence: 80%

“…Additionally, they underscored the need to carefully assess the cross-reactivity of any topoisomerase-directed antibacterial agent against eukaryotic topoisomerases. Studies to address this important question and their implications for potential quinolone toxicity have been discussed in a recent review (13).…”

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Induction of calf thymus topoisomerase II-mediated DNA breakage by the antibacterial isothiazoloquinolones A-65281 and A-65282

Kohlbrenner

Wideburg

Weigl

et al. 1992

Antimicrob Agents Chemother

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A number of quinolones and related antibacterial compounds were screened for activity against calf thymus topoisomerase II by using the P4 unknotting and DNA breakage assays. Several compounds from different structural classes which inhibited DNA unknotting with 50% inhibitory concentrations ranging from 8 to 25 ,ug/ml were identified. Two experimental isothiazoloquinolones from this group, designated A-65281 and A-65282, were also found to induce considerable DNA breakage mediated by calf thymus topoisomerase II, with 32P-end-labeled pBR322 as the substrate. These compounds were nearly as potent as teniposide, with DNA breakage activity evident at concentrations as low as 4 ,ug/ml. However, some differences in DNA cleavage patterns from those with teniposide were evident. These studies have thus identified a new class of agents which have activity against both bacterial and eukaryotic type H topoisomerases. The implications of these data for the selectivity of topoisomerase-directed compounds and the potential toxicity of such compounds developed as antibacterial agents are discussed. topoisomerase II preparations (3,23,25,34,35). A similar pattern of effects has been demonstrated for the quinolone antibacterial agents. Treatment of bacteria with the quinolone prototype, nalidixic acid, results in extensive chromosomal damage (7, 11). Drug-induced DNA breakage can also be catalyzed by purified DNA gyrase (8,10,36). In related studies it was recently demonstrated that additional quinolone-binding sites appear upon the formation of gyrase-DNA complexes and that occupancy of these sites correlates with the occurrence of DNA breakage (30).In general, the agents directed against type II topoisomerases are specific for either bacterial or eukaryotic enzymes. However, in view of the mechanistic similarities and the sequence homologies shared by the bacterial and eukaryotic enzymes, the possibility exists that some agents interact with both classes. Indeed, several antibacterial quinolones which inhibit the P4 DNA-unknotting activity of various eukaryotic type II topoisomerases have been identified (1,15,17). Also, ciprofloxacin and several experimental fluroroquinolones induce topoisomerase II-mediated DNA breakage (1,12,24). These findings raised the possibility that additional classes of compounds that interact with both prokaryotic and eukaryotic enzymes will be identified. Additionally, they underscored the need to carefully assess the cross-reactivity of any topoisomerase-directed antibacterial agent against eukaryotic topoisomerases. Studies to address this important question and their implications for potential quinolone toxicity have been discussed in a recent review (13).We report here the identification of two closely related antibacterial isothiazoloquinolones, designated as A-65281 and A-65282, which are potent inhibitors of the P4-unknotting reaction catalyzed by calf thymus topoisomerase II. Moreover, these compounds are potent inducers of DNA breakage by calf thymus topoisomerase II. These data thus

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Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems

Cited by 92 publications

References 45 publications

Drug and Multidrug Resistance among Mycobacterium leprae Isolates from Brazilian Relapsed Leprosy Patients

Drug and Multidrug Resistance among Mycobacterium leprae Isolates from Brazilian Relapsed Leprosy Patients

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

Induction of calf thymus topoisomerase II-mediated DNA breakage by the antibacterial isothiazoloquinolones A-65281 and A-65282

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