Novel fluorobenzothiazole as a dual inhibitor of gyrase B and topoisomerase IV against Gram-positive pathogens.

Aim: The development of a novel inhibitor targeting gyrase B and topoisomerase IV offers an opportunity to combat multidrug resistance. Methods: We investigated the activity of RBx 10080758 against Gram-positive bacteria in vitro and in vivo. Results: RBx 10080758 showed a potent 50% inhibitory concentration of 0.13 µM and 0.25 µM against gyrase B and topoisomerase IV, respectively, and exhibited strong whole-cell in vitro activity with MIC ranges of 0.015-0.06 and 0.015-0.03 µg/ml against Staphylococcus aureus and Streptococcus pneumoniae, respectively. In a rat thigh infection model with methicillin-resistant S. aureus, RBx 10080758 at 45 mg/kg exhibited a >3 log10 CFU reduction in thigh muscles. Conclusion: RBx 10080758 displayed potent activity against multiple multidrug-resistant Gram-positive bacteria with a dual-targeting mechanism of action.

Consensus recommendations for COVID-19-related myocarditis in athletes: proof of concept-case report.

Background: Post-viral myocarditis has been associated with sudden cardiac death in athletes. Since the beginning of the COVID-19 pandemic, the concern of post-viral myocarditis impacting the professional athletic community has been present. Case summary: An elite-level basketball player presented after a positive COVID-19 test with findings consistent with ventricular tachycardia related to myocardial fibrosis/scar from a COVID-19-related myocarditis. Although rare, COVID-19 myocarditis can occur. This case illustrates how the consensus guidelines for return-to-play correctly identified the player as high risk with appropriate downstream evaluation by cardiac magnetic resonance (CMR) imaging. The stepwise approach is illustrated in this case and highlights the utility and success of the algorithm when approaching athletes with COVID-19-related myocarditis risk and determining a return to exercise. Discussion: Diligence is required to identify competitive athletes with features suggestive of myocarditis at the initial presentation and with the return to exercise. Cardiopulmonary symptoms in the setting of recent COVID-19 infection should prompt additional testing in a stepwise fashion and often benefit from CMR in addition to the triad testing with electrocardiography, echocardiography, and cardiac troponin measurement to further investigate clinical presentations of COVID-19-related myocarditis.

Novel FtsZ inhibitor with potent activity against Staphylococcus aureus.

OBJECTIVES: FtsZ is an essential bacterial protein and an unexplored target for the development of antibacterial drugs. The development of a novel inhibitor targeting FtsZ offers a potential opportunity to combat drug resistance. DS01750413, a new derivative of PC190723, is a novel FtsZ inhibitor with improved in vitro and in vivo activity. The objective of this study was to investigate the efficacy of DS01750413 against Staphylococcus spp., including MRSA, in in vitro and in vivo models. METHODS: In vitro activities of DS01750413 and standard-of-care antibiotics were evaluated against clinical isolates of Gram-positive pathogens. The in vivo efficacy was evaluated in a murine systemic infection model caused by MRSA. RESULTS: DS01750413 showed potent in vitro activity against MRSA clinical isolates with MIC ranges of 0.5-1 mg/L and also demonstrated concentration-dependent bactericidal killing. In the murine bacteraemia infection model of MRSA, treatment with DS01750413 resulted in prolonged survival of animals compared with placebo-treated animals and exhibited a significant reduction in the bacterial load in liver, spleen, lungs and kidneys. CONCLUSIONS: DS01750413 showed encouraging in vitro and in vivo activity against MRSA. As a novel chemical class, DS01750413 has the potential to become clinically viable antibiotics to address the drug resistance problem by its unique novel targeting mechanism of action.

Novel azoles with potent antileishmanial activity.

Aim: To investigate the antileishmanial activity of novel azole compounds against Leishmania donovani, which causes deadly visceral leishmaniasis disease. Materials & methods: A focused azole-based library was screened against both promastigotes and amastigotes forms of L. donovani strains in flat-bottomed 96-well tissue culture plates and J774A.1 macrophage cell-line infected with L. donovani. The comprehensive screening of azole-based library against L. donovani strains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign. Results: Hits identified from azole-based library exhibited potent in vitro activity against promastigotes and amastigotes of L. donovani. Conclusion: These potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for antileishmania program.

Azithromycin Exhibits Activity Against Pseudomonas aeruginosa in Chronic Rat Lung Infection Model.

Pseudomonas aeruginosa forms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected with P. aeruginosa and improved their lung function. The present study was conducted to evaluate the effect of azithromycin on P. aeruginosa biofilm. We show that azithromycin exhibited a potent activity against P. aeruginosa biofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restricted P. aeruginosa biofilm formation by inhibiting the expression of pel genes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronic P. aeruginosa lung infection, we show that azithromycin treatment resulted in the suppression of quorum sensing-regulated virulence factors, significantly improving the clearance of P. aeruginosa biofilms compared to that in the placebo control. We conclude that azithromycin attenuates P. aeruginosa biofilm formation, impairs its ability to produce extracellular biofilm matrix, and increases its sensitivity to the immune system, which may explain the clinical efficacy of azithromycin in cystic fibrosis patients.

Potential of the fluoroketolide RBx 14255 against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae in an experimental murine meningitis model.

BACKGROUND: RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens. OBJECTIVES: To investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model. METHODS: In vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model. RESULTS: RBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model. CONCLUSIONS: RBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.

Effect of DS-2969b, a novel GyrB inhibitor, on rat and monkey intestinal microbiota.

DS-2969b, a novel GyrB inhibitor, transiently and reversibly altered the counts of limited intestinal microbiota at around 10 µg/g of faecal levels in rats and monkeys. Considering the high activity of DS-2969b against Clostridium difficile, 10 µg/g of faecal levels would be sufficient for clearing C. difficile from the intestine.

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus.

DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the in vitro activity of DS-2969b and the in vivo activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of S. aureus DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except for Moraxella catarrhalis and Haemophilus influenzae DS-2969b was active against MRSA with an MIC90 of 0.25 µg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 × 10-10 in all four S. aureus isolates at 4× MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC (fTMIC) correlated best with in vivo efficacy, and the static percent fTMIC was 43 to 49%. A sufficient fTMIC was observed in a phase 1 multiple-ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to-oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid.

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile.

DS-2969b is a novel GyrB inhibitor that is currently under clinical development for the treatment of Clostridium difficile infection (CDI). In this study, the in vitro and in vivo activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity of C. difficile DNA gyrase. DS-2969b showed potent in vitro activity against C. difficile clinical isolates with a MIC90 of 0.06 µg/ml, which was 2-, 32-, and 16-fold lower than the MIC90s of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneously resistant mutants of various C. difficile strains at 4× MIC, and the frequency of resistance development was less than 4.8 × 10-9 In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg of body weight once a day, in contrast to a 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at a 50-mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacious by 5-day subcutaneous administration in the CDI model. DS-2969b showed similar levels of fecal excretion after intravenous and oral administrations in rats. These data support further development of DS-2969b as a drug for oral and intravenous treatment of CDI.

A rare case of dural arteriovenous fistula presenting as primary intraventricular hemorrhage.

Primary intraventricular haemorrhage (PIVH) is rare. Dural arteriovenous fistula causing PIVH is extremely rare. We report a case of a 17 year old boy who presented with left hemiparesis, left lower motor neuron facial palsy and ataxia. His computed tomography head revealed primary intraventricular hemorrhage. Catheter super selective angiography revealed a dural arterio venous fistula with arterial feeder arising from the middle meningeal artery as well as from the inferior marginal tentorial artery. Glue injection led to successful disappearance of the fistula and eventual clinical recovery.

In Vitro and In Vivo Activities of a Bi-Aryl Oxazolidinone, RBx 11760, against Gram-Positive Bacteria.

RBx 11760, a bi-aryl oxazolidinone, was investigated for antibacterial activity against Gram-positive bacteria. The MIC90s of RBx 11760 and linezolid against Staphylococcus aureus were 2 and 4 mg/liter, against Staphylococcus epidermidis were 0.5 and 2 mg/liter, and against Enterococcus were 1 and 4 mg/liter, respectively. Similarly, against Streptococcus pneumoniae the MIC90s of RBx 11760 and linezolid were 0.5 and 2 mg/liter, respectively. In time-kill studies, RBx 11760, tedizolid, and linezolid exhibited bacteriostatic effect against all tested strains except S. pneumoniae RBx 11760 showed 2-log10 kill at 4× MIC while tedizolid and linezolid showed 2-log10 and 1.4-log10 kill at 16× MIC, respectively, against methicillin-resistant S. aureus (MRSA) H-29. Against S. pneumoniae 5051, RBx 11760 showed bactericidal activity, with 4.6-log10 kill at 4× MIC compared to 2.42-log10 and 1.95-log10 kill for tedizolid and linezolid, respectively, at 16× MIC. RBx 11760 showed postantibiotic effects (PAE) at 3 h at 4 mg/liter against MRSA H-29, and linezolid showed the same effect at 16 mg/liter. RBx 11760 inhibited biofilm production against methicillin-resistant S. epidermidis (MRSE) ATCC 35984 in a concentration-dependent manner. In a foreign-body model, linezolid and rifampin resulted in no advantage over stasis, while the same dose of RBx 11760 demonstrated a significant killing compared to the initial control against S. aureus (P < 0.05) and MRSE (P < 0.01). The difference in killing was statistically significant for the lower dose of RBx 11760 (P < 0.05) versus the higher dose of linezolid (P > 0.05 [not significant]) in a groin abscess model. In neutropenic mouse thigh infection, RBx 11760 showed stasis at 20 mg/kg of body weight, whereas tedizolid showed the same effect at 40 mg/kg. These data support RBx 11760 as a promising investigational candidate.

Longitudinally extensive transverse myelitis: A retrospective analysis of sixty-four patients at tertiary care center of North-West India.

OBJECTIVES: To evaluate the demographic profile, clinical presentations, laboratory parameters and etiologies of longitudinally extensive transverse myelitis (LETM) patients in Indian population. PATIENTS AND METHODS: LETM is characterized by contiguous inflammatory lesions of spinal cord extending to three or more vertebral segments. Neuromyelitis optica (NMO) is the most common cause of LETM. In clinical practice, both LETM and NMO are thought to be synonymous with each other because of their very frequent association. Other causes of LETM are infective, neoplastic, autoimmune diseases and connective tissue disorders. All other causes should be ruled out before making the diagnosis of NMO in LETM patients. We conducted a retrospective study from August 2010 to February 2016 and analyzed various demographic profile, clinical presentations, laboratory parameters and etiologies in sixty-four patients of LETM. RESULTS: In our series, majority of the patients presented with acute bladder dysfunction and paraparesis. Twenty-one patients (32.81%) were clinically diagnosed as NMO, out of which thirteen patients were found to have positive serum NMO antibody. Other etiologies of LETM in our series were multiple sclerosis [9 patients], acute disseminated encephalomyelitis (ADEM) [6 patients], postinfectious [5 patient], subacute combined degeneration (SCD) [4 patient], tuberculous myelitis [4 patients], spinal arteriovenous malformation (AVM) [3 patient] and systemic lupus erythematosus (SLE) [3 patient], respectively. In nine patients, cause could not be ascribed despite thorough investigations. CONCLUSION: LETM is a heterogeneous disorder with a varied clinical feature, etiologies and outcome. Even the LETM patients who presented with optic neuritis do not necessarily have NMO. Therefore, the diagnosis of NMO should be made only after excluding other causes of LETM. The presence of NMO-Ab (Aquaporin 4-Ab) predicts the increased risk of recurrence of LETM or conversion to NMO.

Primary intraventricular hemorrhage: clinical features, risk factors, etiology, and yield of diagnostic cerebral angiography.

BACKGROUND: Primary intraventricular hemorrhage (PIVH) is a rare neurological disorder, with bleeding confined to the ventricles only, without recognizable parenchymal or subarachnoid component. AIM: The purpose of this retrospective study was to identify clinical features, predisposing risk factors, etiology, radiological features and yield of diagnostic cerebral angiography in identifying the etiological causes. SETTINGS AND DESIGN: Records of patients admitted in neurology division were analyzed in a tertiary care teaching hospital. MATERIALS AND METHODS: We analyzed the records of 27 patients with PIVH evaluated and treated at our institute from August 2010 to April 2013. PIVH was diagnosed as hemorrhage in the ventricles only, detected by computed tomography scan without evidence of intraparenchymal, subarachnoid hemorrhage or intraventricular hemorrhage associated with trauma. CT angiography (CTA) alone was done in 10 patients (37.03%), digital subtraction angiography (DSA) in 2 patients (7.4%) and both CTA as well as DSA was done in 15 patients (55.5%). STATISTICAL ANALYSIS USED: Categorical and continuous data were analyzed using SPSS version 17. RESULTS: 17 (62.96%) patients were females and 10 (37.03%) were males with ratio of F:M= 1.7:1. Headache was the commonest mode of presentation (85.18%). Hypertension was most common predisposing factor (29.62%) followed by arterio-venous malformations (AVMs) (25.92%), moyamoya disease (MMD) (11.11%), lenticuostriate artery aneurysm (LSA) (11.11%), arterial dissections (7.4%) and dural arteriovenous fistula (dAVF) (3.7%). CONCLUSIONS: PIVH is rare and hypertension is important predisposing factor. Yield of cerebral angiography is high in diagnosing the etiology. AVMs and other rare etiological causes like MMD, LSA aneurysm, arterial dissection, and dAVF should be kept in mind with a high index of suspicion and warrants cerebral angiography in them, as some of the causes are potentially treatable.

A novel ketolide, RBx 14255, with activity against multidrug-resistant Streptococcus pneumoniae.

We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

Hereditary amyloid polyneuropathy in a family from North West India: phenotypic, MRI and pathologic study.

Hereditary amyloid polyneuropathies are rare, heterogeneous group of autosomal dominant disorders and deserve special attention because of its rare presentation, multisystem involvement and significant therapeutic implications if diagnosed early. We report a male patient of hereditary amyloid polyneuropathy from North West India with peripheral nerve, autonomic nervous system, vitreous and cardiac involvement.