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Shabir A Bhat, Iram K Iqbal, Ashwani Kumar
The NADH:NAD(+) ratio is the primary indicator of the metabolic state of bacteria. NAD(H) homeostasis is critical for Mycobacterium tuberculosis (Mtb) survival and is thus considered an important drug target, but the spatio-temporal measurements of NAD(H) remain a challenge. Genetically encoded fluorescent biosensors of the NADH:NAD(+) ratios were recently described, paving the way for investigations of the metabolic state of pathogens during infection. Here we have adapted the genetically encoded biosensor Peredox for measurement of the metabolic state of Mtb in vitro and during infection of macrophage cells...
2016: Frontiers in Cellular and Infection Microbiology
Elizabeth P Harausz, Anthony J Garcia-Prats, James A Seddon, H Simon Schaaf, Anneke C Hesseling, Jay Achar, Jonathan Bernheimer, Andrea Cruz, Lia D'Ambrosio, Anne Detjen, Stephen M Graham, Jennifer Hughes, Sylvie Jonckheere, Ben J Marais, Giovanni Battista Migliori, Lindsay McKenna, Alena Skrahina, Marina Tadolini, Peyton Wilson, Jennifer Furin
It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents...
November 17, 2016: American Journal of Respiratory and Critical Care Medicine
Giovanni Sotgiu, Simon Tiberi, Rosella Centis, Lia D'Ambrosio, Zhenia Fuentes, Alimuddin Zumla, Giovanni Battista Migliori
In spite of the recent introduction of two new drugs (delamanid and bedaquiline) and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB), clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as Bangladesh regimen) proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high dose isoniazid and ethambutol followed by 5 months of moxifloxacin, clofazimine, pyrazinamide and ethambutol...
November 2, 2016: International Journal of Infectious Diseases: IJID
Winnie Szeto, Monica T Garcia-Buitrago, Lilian Abbo, Joseph D Rosenblatt, Baharak Moshiree, Michele I Morris
Clofazimine-induced crystal-storing histiocytosis is a rare complication of treatment previously reported in dermatology literature as a complication of leprosy therapy. We report a case of disseminated Mycobacterium abscessus requiring treatment with high-dose oral clofazimine resulting in enteropathy in a patient who presented with abdominal pain, malnutrition, and melena.
September 2016: Open Forum Infectious Diseases
Moloko C Cholo, Maborwa T Mothiba, Bernard Fourie, Ronald Anderson
Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treatment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the 're-purposed' riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis...
October 20, 2016: Journal of Antimicrobial Chemotherapy
Nicole C Ammerman, Rosemary V Swanson, Asa Tapley, Chivonne Moodley, Bongani Ngcobo, John Adamson, Afton Dorasamy, Sashen Moodley, Zinhle Mgaga, Linda A Bester, Sanil D Singh, Deepak V Almeida, Jacques H Grosset
OBJECTIVES: The anti-leprosy drug clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and has been associated with treatment-shortening activity in both clinical and preclinical studies of TB chemotherapy. However, a reported lack of early bactericidal activity (EBA) in TB patients has raised questions regarding the usefulness of clofazimine as an anti-TB drug. Our objective was to systematically evaluate the EBA of clofazimine in vitro and in vivo to provide insight into how and when this drug exerts its antimicrobial activity against M...
October 25, 2016: Journal of Antimicrobial Chemotherapy
Blanca María Morfín-Maciel, María Carmen Jiménez Martínez
BACKGROUND: Leprosy is a chronic granulomatous infection that affects skin and peripheral nerves. Its prevalence has declined, but is still observed mainly in poor rural areas. CASE REPORT: A male city dweller with photophobia and chronic dermatosis in the face: nodular and erythematous lesions, pustules, keratitis and entropion, partial eyebrows loss, and edema on eyelids, chin, and nose bridge. The rest of the body had no lesion or lymphadenopathy. Biopsy revealed Langhans giant cell proliferation in the superficial dermis without epidermal atrophy...
October 2016: Revista Alergia Mexico: Organo Oficial de la Sociedad Mexicana de Alergia e Inmunología, A.C
Ahmad Qasem, Mitra Safavikhasraghi, Saleh A Naser
BACKGROUND: Most recently we reported that RHB‑104 triple antibiotics combination in culture is bactericidal and should be effective for treatment of Crohn's disease (CD)-associated with Mycobacterium avium subspecies paratuberculosis (MAP) (Alcedo et al. in Gut Pathog 14:32, 2016). The combination exhibited unique synergistic antimicrobial growth activity. The proprietary RHB-104 capsule formulation contains active ingredients (63.3 % Clarithromycin (CLA), 6.7 % Clofazimine (CLO) and 30 % Rifabutin (RIF))...
2016: Gut Pathogens
Nirupama Kasturi, Renuka Srinivasan
A 26-year-old male vitiliginous patient presented with decreased visual acuity because of a central scotoma in the left eye with no significant retinal changes on fundus examination. In this case report, a diagnosis of possible drug-induced premaculopathy was made, and the drugs were withdrawn. On the follow-up, after 3 months, the visual acuity in the left eye gradually improved. Early suspicion of drug-induced maculopathy and withdrawal of the drug may prevent the progression of maculopathy.
July 2016: Journal of Pharmacology & Pharmacotherapeutics
Onivola Raharolahy, Lala S Ramarozatovo, Irina M Ranaivo, Fandresena A Sendrasoa, Malalaniaina Andrianarison, Mala Rakoto Andrianarivelo, Emmanuelle Cambau, Fahafahantsoa Rapelanoro Rabenja
We report a case of misdiagnosed leprosy in a 21-year-old Malagasy male, who, improperly treated, developed secondary mycobacterial resistance to fluoroquinolone. The patient contracted the infection 9 years prior to the current consultation, displaying on the right thigh a single papulonodular lesion, which progressively spread to the lower leg, back, and face. Initial administration of ciprofloxacin and prednisolone led to temporary and fluctuating improvement. Subsequent long-term self-medication with ciprofloxacin and corticosteroid did not heal the foul and nonhealing ulcers on the legs and under the right sole...
2016: Case Reports in Infectious Diseases
Dhiraj Kumar Singh, Ved Prakash Dwivedi, Anand Ranganathan, William R Bishai, Luc Van Kaer, Gobardhan Das
Tuberculosis (TB) is the oldest known infectious disease, yet there is no effective vaccine against adult pulmonary TB. Emerging evidence indicates that T helper (Th)1 and Th17 cells play important roles in host protection against TB. However, TB vaccine efficacy in mice is critically dependent on the balance between antigen-specific central memory T (Tcm) to effector memory T (Tem) cells. Specifically, a high Tcm to Tem cell ratio is essential for optimal vaccine efficacy. Here, we show that pharmacological inhibition of Kv1...
August 28, 2016: Journal of Infectious Diseases
Z Ozturk, A Tatliparmak
Leprosy is a chronic disease which primarily affects the skin, mucous membranes and peripheral nerves due to Mycobacterium leprae. It is now infrequent in Europe and is rarely reported during pregnancy. Leprosy can be exacerbated during pregnancy, and without treatment it can permanently damage the skin, nerves, limbs and eyes. Therefore, it is important to treat leprosy during pregnancy. This article describes a patient with multibacillary lepromatous leprosy who was treated with multidrug therapy during pregnancy and breastfeeding...
August 23, 2016: Dermatologic Therapy
Angela Zaccagnino, Antonella Managò, Luigi Leanza, Artur Gontarewitz, Bernhard Linder, Michele Azzolini, Lucia Biasutto, Mario Zoratti, Roberta Peruzzo, Karen Legler, Anna Trauzold, Holger Kalthoff, Ildiko Szabo
Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations...
August 16, 2016: Oncotarget
Yu-Min Chuang, Noton K Dutta, Chien-Fu Hung, T-C Wu, Harvey Rubin, Petros C Karakousis
Mycobacterium tuberculosis (Mtb) remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of Mtb persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate (poly(P)) is a key regulatory molecule in the Mtb stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in Mtb, while the exopolyphosphatases PPX1 and PPX2, and the GTP synthase PPK2 are responsible for poly(P) hydrolysis...
August 15, 2016: Antimicrobial Agents and Chemotherapy
Dirk A Lamprecht, Peter M Finin, Md Aejazur Rahman, Bridgette M Cumming, Shannon L Russell, Surendranadha R Jonnala, John H Adamson, Adrie J C Steyn
The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb's respiration using extracellular flux technology. We find that Mtb's ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels...
August 10, 2016: Nature Communications
Petrease H Patton, Claire E Parker, John K MacDonald, Nilesh Chande
BACKGROUND: There have been a number of studies with conflicting results which have examined the effect of anti-tuberculous therapy in Crohn's disease. A meta-analysis was performed to evaluate the use of anti-tuberculous therapy for the maintenance of remission in Crohn's disease. OBJECTIVES: To evaluate the effects of anti-tuberculous therapy for the maintenance of remission in patients with Crohn's disease. SEARCH METHODS: We searched MEDLINE, EMBASE, the Cochrane LIbrary, and the Cochrane IBD Group Specialized Register from inception to June 22, 2015...
2016: Cochrane Database of Systematic Reviews
Shengke Li, Judy Yuet-Wa Chan, Yan Li, David Bardelang, Jun Zheng, Wing Wai Yew, Denise Pui-Chung Chan, Simon Ming Yuen Lee, Ruibing Wang
Cucurbit[7]uril (CB[7]) has recently attracted increasing attention in pharmaceutical sciences due to its great potential in improving the physicochemical properties and bioactivity of drug molecules. Herein, we have investigated the influence of CB[7]'s complexation on the solubility, antimycobacterial activity, and cardiotoxicity of a model anti-tuberculosis drug, clofazimine (CFZ), that has poor water-solubility and inherent cardiotoxicity. In our study, CFZ was found to be complexed by CB[7], in a 1 : 1 binding mode with a relatively strong binding affinity (in the order of magnitude of 10(4)-10(5) M(-1)), as determined by the phase solubility method via HPLC-UV analysis and (1)H NMR titration, as well as UV-visible spectroscopic titration, and further confirmed by electrospray ionization mass spectrometry (ESI-MS)...
August 21, 2016: Organic & Biomolecular Chemistry
Kamal Ahmed, Holly V Shaw, Alexey Koval, Vladimir L Katanaev
Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed drugs currently exist, and only very few candidates have reached early phase clinical trials. Among different strategies to develop WNT-targeting anti-cancer therapies, repositioning of existing drugs previously approved for other diseases is a promising approach...
July 14, 2016: Cancers
Mohammad Rehan Ajmal, Sumit Kumar Chaturvedi, Nida Zaidi, Parvez Alam, Masihuz Zaman, Mohammad Khursheed Siddiqi, Saima Nusrat, Mohammad Sarwar Jamal, Mohamed H Mahmoud, Gamal Badr, Rizwan Hasan Khan
The present study details the binding process of clofazimine to hen egg white lysozyme (HEWL) using spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM) and molecular docking techniques. Clofazimine binds to the protein with binding constant (Kb) in the order of 1.57x10(4) at 298K. Binding process is spontaneous and exothermic. Molecular docking results suggested the involvement of hydrogen bonding and hydrophobic interactions in the binding process. Bacterial cell lytic activity in the presence of clofazimine was increased to more than 40% of the value obtained with HEWL only...
July 11, 2016: Journal of Biomolecular Structure & Dynamics
Arnold Mafukidze, Elizabeth Harausz, Jennifer Furin
INTRODUCTION: Drug-resistant forms of tuberculosis are a major public health problem with a serious global impact. Although there have recently been two new drugs introduced for the treatment of drug-resistant TB (bedaquiline and delamanid), the current therapeutic armamentarium is limited. Because treatment of drug-resistant TB requires the use of a multidrug-regimen, there has been growing interest in the use of antibiotics developed for other infectious pathogens but that have shown efficacy in the treatment of TB...
July 18, 2016: Expert Review of Clinical Pharmacology
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