Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Effect of topical vancomycin powder on surgical site infection prevention in major orthopaedic surgery: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: Evidence has been mixed regarding the effect of topical vancomycin (VCM) powder in reducing surgical site infection (SSI). AIM: To clarify the effect of topical VCM powder for the prevention of SSI in major orthopaedic surgeries. METHODS: The MEDLINE, Embase, CENTRAL, ICTRP, and ClinicalTrials.gov databases were searched from their inception to September 25th, 2023. Randomized controlled trials comparing topical VCM powder and controls for the prevention of SSI in major orthopaedic surgeries were included. Two reviewers independently screened the title and abstract and extracted relevant data, followed by the assessment of the risk of bias and the certainty of the evidence. Main outcome measures were overall SSI, reoperation, and adverse events. Summary results were obtained using random-effects meta-analysis. Trial sequential analysis (TSA) was performed. FINDINGS: Eight randomized controlled trials yielded data on 4307 participants. VCM powder showed no difference in reducing overall SSI. The cumulative number of patients did not exceed the required information size of 19,233 in our TSA, and the Z-curves did not cross the trial sequential monitoring or futility boundary, suggesting an inconclusive result of the meta-analysis. No difference was found for reoperation. Among SSIs, VCM powder showed a statistically significant difference in reducing Gram-positive cocci SSI. However, the certainty of this evidence was very low. CONCLUSION: This systematic review and meta-analysis suggests inconclusive results regarding the effect of VCM powder in reducing SSI in major orthopaedic surgeries. Further trials using rigorous methodologies are required to elucidate the effect of this intervention.

The role of histology in the diagnosis of spondylodiscitis: correlation with clinical and microbiological findings.

AIMS: The aim of this study was to determine the diagnostic utility of histological analysis in spinal biopsies for spondylodiscitis (SD). PATIENTS AND METHODS: Clinical features, radiology, results of microbiology, histology, and laboratory investigations in 50 suspected SD patients were evaluated. In 29 patients, the final (i.e. treatment-based) diagnosis was pyogenic SD; in seven patients, the final diagnosis was mycobacterial SD. In pyogenic SD, the neutrophil polymorph (NP) infiltrate was scored semi-quantitatively by determining the mean number of NPs per (×400) high-power field (HPF). RESULTS: Of the 29 pyogenic SD patients, 17 had positive microbiology and 21 positive histology (i.e. one or more NPs per HPF on average). All non-SD patients showed less than one NP per HPF. The presence of one or more NPs per HPF had a diagnostic sensitivity of 72.4%, specificity 100%, accuracy 100%, positive predictive value (PPV) 81.0%, and negative predictive value (NPV) 61.9%. Sensitivity, specificity, and accuracy were greater using the criterion of positive histology and/or microbiology than positive histology or microbiology alone. Granulomas were identified histologically in seven mycobacterial SD patients, and positive microbiology was detected in four. CONCLUSION: The diagnosis of pyogenic SD was more often confirmed by positive histology (one or more NPs per HPF on average) than by microbiology, although diagnostic sensitivity was greater when both histology and microbiology were positive. Cite this article: Bone Joint J 2019;101-B:246-252.

Localised foot and ankle amyloid deposition.

BACKGROUND: Localised (transthyretin-associated) amyloid is commonly seen in articular/periarticular tissues of elderly individuals. Whether age-associated, amyloid deposition occurs in foot and ankle (F&A) tissues has not previously been investigated. In this study we assessed the nature and frequency of F&A amyloid deposition and determined whether it is associated with age and/or specific articular/periarticular F&A lesions. METHODS: Histological sections of twenty five normal F&A articular/periarticular tissues (16-71 years) and a range of F&A lesions were stained by Congo Red. The amyloid protein was identified by immunohistochemistry and type of matrix glycosaminoglycans determined by Alcian Blue (critical electrolyte concentration) histochemistry. RESULTS: Amyloid deposits were found in the joint cartilage and capsule of 3/25 normal specimens (57, 62 and 78 years). Amyloid deposits were small, contained transthyretin, and found in areas of matrix degeneration associated with the presence of highly sulphated glycosaminoglycans. In patients older than 47 years, small amyloid deposits were noted in some F&A lesions, including osteoarthritis, Charcot arthropathy, bursa, ganglion, chondrocalcinosis, gout, calcific tendonitis and Achilles tendonitis. CONCLUSION: Small localised amyloid deposits in F&A tissues contain transthyretin and occur in areas of matrix degeneration associated with the presence of highly sulphated glycosaminoglycans; these deposits are age-associated and, although seen more commonly in some F&A lesions, are small and unlikely to be of pathogenic significance.

Survival of Brånemark System Mk III implants and analysis of risk factors associated with implant failure.

The purpose of this study was to retrospectively investigate the outcomes of Brånemark System Mk III TiUnite/Groovy implants placed in patients at Kobe University Hospital. Various risk factors for implant failure, including mechanical coupling, were investigated by univariate and multivariate analysis. The predictive variables investigated included age, sex, smoking habit, general health, history of radiation therapy, application of a dentomaxillary prosthesis, type of prosthesis, use of alveolar bone augmentation, site of implant insertion, mechanical coupling between implants, and the length and diameter of the implants. Of the 907 implants investigated, only 23 were unsuccessful; the overall survival rate was 96.7%. Increased age, radiation therapy, application of a removable prosthesis or dentomaxillary prosthesis, lack of mechanical coupling between implants, and shorter implants (≤8.5mm) were significant risk factors for implant failure according to univariate analysis (P<0.05). Multivariate analysis identified a significant association (P<0.05) between dental implant failure and a lack of mechanical coupling between implants (odds ratio 6.88) and shorter implants (≤8.5mm) (odds ratio 3.43). The findings of this study demonstrated multivariate relationships between various risk factors and dental implant failure.

Neurotrophin-3 increases the DNA-binding activities of several transcription factors in a mouse osteoblastic cell line.

In the mouse osteoblastic cell line MC3T3-E1, the signaling responses of several DNA-binding proteins induced by the treatment of neurotrophin-3 were examined using electrophoretic mobility shift assay. Neurotrophin-3 increased binding activities in nuclear extracts of MC3T3-E1 cells to TPA-responsive element (TRE), cyclic AMP-responsive element (CRE) and serum-responsive element (SRE), but not binding activity in the nuclear extracts to c-Myc binding DNA element. Competition experiments revealed that the binding activity to TRE in the nuclear extracts of neurotrophin-3-treated MC3T3-E1 cells was entirely inhibited by the both unlabeled TRE and CRE probes. On the other hand, the binding activity to CRE was abolished by the unlabeled CRE probe but not by the same amount of unlabeled TRE probe. Moreover, immunodepletion/supershift assay using antibodies directed to Fos, Jun and CREB proteins, showed that the binding activities to TRE and CRE in the nuclear extracts were derived in part from these proteins.

Different effects of oxidative stress on activation of transcription factors in primary cultured rat neuronal and glial cells.

We compared the cytotoxic effects of oxidative stress on neuronal and glial cells in vitro by examining the cell viability and changes in DNA-binding activities of transcription factors, AP-1 and CREB, using Trypan blue exclusion and electrophoretic mobility shift assay (EMSA), respectively. Neurotoxin 6-hydroxydopamine (6-OHDA) and H2O2 reduced the viability of both types of cells in time- and concentration-dependent manner. Both neurotoxins dose-dependently decreased DNA-binding activities in neuronal cells. The results of cell viability assay suggested that these changes may reflect the reduction in neuronal cell viability. In contrast, both reagents increased DNA-binding activities in glial cells, although they decreased cell numbers. These results suggest that the effects of oxidative stress on transcription factors is different in neuronal and glial cells. We also examined the effect of brain-derived neurotrophic factor (BDNF) on 6-OHDA- or H2O2-induced changes in DNA-binding activities. In neuronal cells, pre-treatment with BDNF prevented the decrease in DNA-binding activities induced by 6-OHDA or H2O2. In glial cells, the effect of BDNF on oxidative stress-induced changes in DNA-binding activities in the 6-OHDA-treated group were opposite to those in H2O2-treated group. Our results suggest that 6-OHDA and H2O2 may exert their cytotoxic mechanisms through different signal transduction systems.

Effects of single cyclosporin A pretreatment on pentylenetetrazol-induced convulsion and on TRE-binding activity in the rat brain.

Using electrophoretic mobility-shift assay (EMSA), we examined changes in DNA-binding activities of transcriptional factor-activated protein-1 (AP-1), which is a Fos-Jun protein complex, onto its responsive element TRE in the hippocampus and amygdaloid nucleus of rats stimulated with pentylenetetrazol (PTZ) injection, and also investigated the effects of a single administration of the immunosuppressant cyclosporin A (CsA). In EMSA with nuclear extracts from the rat brain, the TRE-binding activity of AP-1 in the hippocampus and amygdaloid nucleus markedly increased 2 h after the PTZ injection (75 mg/kg, i.p.). These PTZ-induced increases of the TRE-binding protein in these regions were completely suppressed, by pretreatment with CsA (5 mg/kg, s.c.) 1 h before the PTZ injection. In addition, the administration of CsA significantly ameliorated PTZ-induced convulsion. This therapeutic effect of single CsA pretreatment may be based, in part, on the effects on the TRE-binding activity of AP-1 in the brain. Since single pretreatment of CsA in the present study had no effect on the PTZ-induced induction of c-fos mRNA, c-jun mRNA, Fos protein nor Jun protein, the inhibitory effects of single CsA administration on PTZ-induced TRE-binding activity in the brain may be related to the effects of CsA on AP-1 itself. These results suggest that an immune response via activation of transcriptional factor in the brain tissue is involved in the convulsion.

Alterations of cAMP response element-binding activity in the aged rat brain in response to administration of rolipram, a cAMP-specific phosphodiesterase inhibitor.

Transcription factor, cAMP response element-binding protein (CREB), which is phosphorylated by cAMP-dependent kinase via an increase in cAMP, and regulates gene transcription by binding to the cAMP response element (CRE) on target genes. We examined age-dependent alterations in the DNA-binding activity of CREB in rat brain regions, and the effects of rolipram, a cAMP-specific phosphodiesterase (PDE) inhibitor on the CRE-binding activity by electrophoretic mobility-shift assay (EMSA). A marked age-dependent decrease in the CRE-binding activity was shown in all brain regions examined, especially in the basal forebrain, the striatum and the hippocampus. Furthermore, CRE-binding activities in the basal forebrain of both young-adult and aged rats significantly increased 2 h after rolipram administration (1 mg/kg, i.p.), and the rolipram treatment recovered the decreased CRE-binding activity in the aged rats. The saturation experiment in EMSA also revealed that rolipram reversed the decrease in the maximum CRE-bindings in the basal forebrain with aging. Since the 5' upstream region of the rat choline acetyltransferase (ChAT) gene contains CRE, and ChAT-positive neurons in the basal forebrain project to the frontal cortex and the hippocampus, rolipram may exert its previously reported ameliorating effect on the age-related reductions of ChAT activities in the frontal cortex and the hippocampus by phosphorylating CREB in the basal forebrain with activation of cAMP-dependent protein kinase via inhibition of PDE.

Cyclosporin A prevents ischemia-induced reduction of muscarinic acetylcholine receptors with suppression of microglial activation in gerbil hippocampus.

We previously reported the late onset reduction of muscarinic acetylcholine receptors (LORMAR) which begins 7 days after a 5-min period of experimentally induced forebrain ischemia in the gerbil hippocampus. This study demonstrated that post-ischemic administration of cyclosporin A (CsA) reduced LORMAR 10 days after 5 min of forebrain ischemia in the gerbil hippocampus, suggesting that immunosuppression by CsA may reduce damage to the cholinergic system after ischemia. Microglia positive for HLA-DR class II antigen which presented in the hippocampal CA1 area, the region most vulnerable to ischemia, were also reduced by CsA. CsA may suppress microglial activation especially with regard to the antigen-presenting function, and LORMAR may be attenuated by this modulation of microglial function.

Preventive effects of bifemelane hydrochloride on decreased levels of muscarinic acetylcholine receptor and its mRNA in a rat model of chronic cerebral hypoperfusion.

Changes in muscarinic acetylcholine receptor (mACh-R) binding and muscarinic cholinergic m1 receptor (m1-R) mRNA levels were determined in a rat model of cerebral hypoperfusion in which hypoperfusion was induced by permanent bilateral occlusion of the common carotid arteries. After 6 weeks of hypoperfusion, mACh-R binding activity was significantly reduced in the frontal cortex (79.0 percent, P <0.01), striatum (74.2 percent, P < 0.01) and hippocampus (78.6 percent, P < 0.01), and the m1-R mRNA levels in the frontal cortex (86.6 percent, P < 0.05) and striatum (89.4 percent, P < 0.05) compared with sham-operated control. Repeated administration of bifemelane hydrochloride (15 mg/kg/day, p.o., once a day from the day of operation for 6 weeks) prevented the hypoperfusion-induced loss of mACh-R binding and m1-R mRNA levels above described. Since the central cholinergic systems play an important role in learning and memory, these findings suggest that bifemelane hydrochloride is useful to treat and/or prevent vascular dementia which is closely related to cerebral hypoperfusion.

Effects of repeated cyclosporin A administration on iminodipropionitrile-induced dyskinesia and TRE-/CRE-binding activities in rat brain.

To clarify the involvement of immunophilin ligands in the pathogenesis and pathophysiology of dyskinesia, we examined the effects of repeated administration of cyclosporin A (CsA) on rat dyskinesia induced by repeated injection of iminodipropionitrile (IDPN 100 mg/kg, i.p., for 7 days). The addition of CsA treatment (5 mg/kg, s.c., 1 h before each IDPN injection) exacerbated IDPN-induced dyskinesia. In the group treated with both CsA and IDPN, the concentration of dopamine was significantly increased in the striatum and nucleus accumbens compared with the group treated with IDPN alone. Furthermore, in the electrophoretic mobility shift assay, the injection of CsA + IDPN increased binding activities of transcription factors to the TPA (12-O-tetradecanoylphorbol-13-acetate)-responsive element (TRE) and to the cAMP response element (CRE) in the striatum and nucleus accumbens, compared with those in rats treated with IDPN alone. The levels of D1-receptor mRNA in the striatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings suggest that the behavioral aggravation of the IDPN-induced dyskinesia caused by CsA administration may be due to the acceleration of the pre- and post-synaptic dopaminegic systems via activation of transcription factors which bind upstream to tyrosine hydroxylase and D1-receptor genes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia.

Late-onset lipid peroxidation and neuronal cell death following transient forebrain ischemia in rat brain.

We previously reported that iron deposition was seen in the cerebral cortex and hippocampal CA1 area late after transient forebrain ischemia generated by four-vessel occlusion in rats. Iron deposition in the hippocampal CA1 area was coupled with delayed pyramidal cell death, while that in the cerebral cortex was not accompanied by neuronal death or atrophy until 6 months after ischemia. Iron is involved in the formation of free radicals, thus contributing to lipid peroxidation. To elucidate whether this iron has deleterious effects on neurons, we investigated changes in the levels of lipid peroxidation and resulting neuronal damage in this ischemia model. The level of malondialdehyde plus 4-hydroxynonenal as major decomposition products of lipid peroxidation, monitored for 6 months beginning just after 30 min of transient forebrain ischemia, was significantly increased in the cerebral cortex at 6 months, and in the striatum from 1 week to 6 months compared to that in sham-operated controls. Histological changes were also examined up to 1 year after reperfusion by immunohistochemical methods. In contrast with the hippocampus and striatum, the cerebral cortex did not develop severe neuronal cell death and atrophy until 1 year after the ischemic insult. We showed that lipid peroxidation took place not only immediately after ischemia-reperfusion but also late after the ischemic insult in regions where iron was deposited, and we showed that neuronal cell death in the cerebral cortex appeared extremely late, suggesting that iron-mediated lipid peroxidation may be of importance in some slowly progressive forms of neurodegeneration.

Pergolide scavenges both hydroxyl and nitric oxide free radicals in vitro and inhibits lipid peroxidation in different regions of the rat brain.

The free radical hypothesis for the pathogenesis and/or progression of Parkinson's disease (PD) has gained wide acceptance in recent years. Although it is clear that dopamine (DA) agonists cannot completely replace levodopa therapy, they can be beneficial early in the course of PD by reducing the accumulation of DA which undergoes auto-oxidation and generates cytotoxic free radicals. In the present study we demonstrate that pergolide, a widely used DA agonist, has free radical scavenging and antioxidant activities. Using a direct detection system for nitric oxide radical (NO.) by electron spin resonance (ESR) spectrometry in an in vitro .NO-generating system, we examined the quenching effects of pergolide on the amount of NO. generated. Pergolide dose-dependently scavenged NO.. In the competition assay, the IC50 value for pergolide was estimated to be about 30 microM. Pergolide also dose-dependently attenuated the hydroxyl radical (.OH) signal in an in vitro FeSO4-H2O2 ESR system with an approximate IC50 value of 300 microM. Furthermore, this agent significantly inhibited phospholipid peroxidation of rat brain homogenates in in vitro experiments and after repeated administration (0.5 mg/kg/24 h, i.p. for 7 days). Our findings suggest a neuroprotective role for pergolide on dopaminergic neurons due to its free radical scavenging and antioxidant properties.

Protective effects of nicergoline against hydrogen peroxide toxicity in rat neuronal cell line.

We examined the effects of nicergoline on hydrogen peroxide (H2O2)-induced neurotoxicity in cultured rat neuronal cell line (B50). H2O2 induced death of B50 cells in a dose-dependent manner. The H2O2-induced neuronal cell death was significantly decreased in B50 cells maintained in the presence of nicergoline. We compared the levels of antioxidants (glutathione, catalase and superoxide dismutase) in nicergoline-treated and untreated B50 cells. Lipid peroxidation products (thiobarbituric acid reactive substances, TBARS) levels were also measured. Cultures treated with nicergoline had higher levels of catalase activity. TBARS level was significantly lower in nicergoline-treated cells than in untreated cells. Our results suggest that nicergoline may induce the up-regulation of intracellular antioxidant defences and protect the neuronal cells against oxidative stress.

Age-related changes in composition of transcription factor, AP-1 complex in the rat brain.

We examined age-related changes in composition of transcription factor, activator protein-1 (AP-1) which binds to TPA responsive element (TRE) in the non-stimulated rat brain, using electrophoretic mobility-shift assay with immunodepletion/supershift assay. The total TRE-binding activity in the frontal cortex and the hippocampus of the aged rats markedly decreased to 66% and 43%, respectively, and TRE-bindings of AP-1 in both regions also decreased to 82% and 66%, respectively, with aging. Jun-Jun dimers accounted for approximately half of the total TRE-bindings and 80-90% of the AP-1 bindings, while there were fewer Fos-Jun dimers, in both examined regions of the non-stimulated adult. The proportion of active Fos-Jun heterodimers in the frontal cortex increased to up to half of the AP-1 bindings in the aged rats, indicating that cortical AP-1-related transcription may increase with aging even under the non-stimulated condition. In the hippocampus, inactive Jun-Jun homodimers became predominant in AP-1 with aging. This regional diversity of age-related changes in the composition of AP-1 in the brain may be related to changes or dysfunction in neuronal signal transduction in the aged.

The association of Pro12Ala polymorphism in PPARgamma2 with lower carotid artery IMT in Japanese.

In this study, the association of the Pro12Ala peroxisome proliferator-activated receptor gamma2 (PPARgamma2) polymorphism with atherosclerosis was examined in a Japanese Type 2 diabetic population. PPARgamma has been identified as a key regulator of adipogenesis. Recently, some studies reported that the Pro12Ala polymorphism was associated with resistance to Type 2 diabetes. It is well-known that Type 2 diabetes is closely related with disorder of lipid metabolism as well as impaired glucose homeostasis, resulting in atherosclerosis. We aimed to evaluate the association between carriers of the Pro12Ala PPARgamma2 mutation and clinical profiles concerning atherosclerosis besides plasma glucose and lipid concentrations. Screening for the mutation was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method among 154 Type 2 diabetic patients. The homozygotes of the Pro12 allele were 143 (93%), the heterozygotes of the Pro12 and Ala12 allele were 11 (7%) and the homozygote of the Ala12 allele was not detected. The group with the Ala12 allele had a significantly lower value of carotid artery intima-media thickness (IMT) than that without it, although there was no difference between two groups in sex, age or other clinical variables we examined. The Pro12Ala PPARgamma2 polymorphism may be associated with carotid artery IMT values in Type 2 diabetes mellitus.

CJ-12,371 and CJ-12,372, two novel DNA gyrase inhibitors. Fermentation,isolation, structural elucidation and biological activities.

A fermentation broth of an unidentified fungus (N983-46) was found to produce DNA gyrase inhibitors, CJ-12,371 (1) and CJ-12,372 (2). Following isolation by solvent extraction and silica gel and ODS (reverse phase) chromatographies, the structures were determined to be novel spiro-ketal compounds with S-configuration at position C-1. CJ-12,371 and CJ-12,372 inhibit both DNA supercoiling and relaxation mediated by Escherichia coli DNA gyrase. The interaction of these compounds with DNA gyrase appears to be novel in that the compounds inhibit supercoiling and relaxation without blocking religation; thus, no cleavage intermediate of double strand DNA is observed. Both compounds have antibacterial activity against several species of pathogenic Gram-positive bacteria, with MICs between 25 and 100 micrograms/ml. These results suggest that the antibacterial potency of CJ-12,371 and CJ-12,372 is attributed to the inhibition of DNA gyrase. However, the compounds did not inhibit DNA gyrase selectively, as they also inhibited eukaryotic topoisomerase II-mediated relaxation. Semi-synthetic modifications to the dihydroxy motif in CJ-12,371 altered both gyrase- and topoisomerase II-inhibitory activities, but did not enhance selectivity.