Pharmacokinetic and
            <i>In Vivo</i>
            Efficacy Studies of the Mycobactin Biosynthesis Inhibitor Salicyl-AMS in Mice

Lun, Shichun; Guo, Haidan; Adamson, John; Cisar, Justin S.; Davis, Thomas B.; Chavadi, Sivagami Sundaram; Warren, Joel; Quadri, Luis E. N.; Tan, Derek S.; Bishai, William R.

doi:10.1128/aac.00918-13

Cited by 48 publications

(57 citation statements)

References 14 publications

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“…The most successful projects have produced pico- and nanomolar inhibitors that show iron-dependent growth inhibition of the targeted pathogen when the pathogen is grown in culture. Testing in animal models, like that highlighted herein for the salicyl-AMS inhibitor [42], is the next necessary step for most of these translational projects [110]. …”

Section: Discussionmentioning

confidence: 99%

“…These extensive structure-activity studies yielded compounds of comparable or worse values for enzyme inhibition and bacterial growth inhibition when compared to the parent compound. Salicyl-AMS has subsequently been shown to be effective in significantly inhibiting M. tuberculosis growth in a mouse model; however, the compound was toxic to the mice at the higher dose (~17 mg/kg), which was proposed to be the result of off-target effects [42]. …”

Section: Inhibitors Of Nrps Biosynthesismentioning

confidence: 99%

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Breaking a pathogen's iron will: Inhibiting siderophore production as an antimicrobial strategy

Lamb

2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The rise of antibiotic resistance is a growing public health crisis. Novel antimicrobials are sought, preferably developing nontraditional chemical scaffolds that do not inhibit standard targets such as cell wall synthesis or the ribosome. Iron scavenging has been proposed as a viable target, because bacterial and fungal pathogens must overcome the nutritional immunity of the host to be virulent. This review highlights the recent work toward exploiting the biosynthetic enzymes of siderophore production for the design of next generation antimicrobials.

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Section: Discussionmentioning

confidence: 99%

Section: Inhibitors Of Nrps Biosynthesismentioning

confidence: 99%

Breaking a pathogen's iron will: Inhibiting siderophore production as an antimicrobial strategy

Lamb

2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…91 Entretanto, apesar das características farmacodinâmicas promissoras, a molécula demonstrou características farmacocinéticas inadequadas, como baixa biodisponibilidade e tempo de meia vida reduzido (t 1/2 = 11 min). 94 Estudos adicionais descreveram um inibidor (35) (Figura 12) da enzima MbtA com CIM 99 de 0,78 μmol L -1 contra cepas de MTB H 37 Rv e melhores propriedades farmacocinéticas (t 1/2 = 62 min) que o seu análogo (34). 95 Outro alvo envolvido na captura de ferro é o EccB3, o qual é um componente do sistema de secreção ESX-3 tipo VII.…”

Section: Alvos Envolvidos Com O Metabolismo Do Ferrounclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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“…Proof-of-concept in vivo efficacy was also demonstrated; however, 1 suffers from poor physicochemical properties that result in high clearance and low oral bioavailability. 10 To further advance this new class of antibiotics, we previously explored a large number of modifications to 1 . 8,11–16 The 2′-Fluoro analogue 2 emerged as a lead compound with improved in vitro antitubercular activity (2-fold more potent than 1 ) while displaying enhanced in vitro (Caco-2 permeability of 4.2 × 10 −6 cm/s or 3.5-fold greater than 1 , indicative of a medium-permeable compound) and in vivo drug disposition properties (3-fold reduced clearance resulting in a commensurate 3-fold improved oral exposure relative to 1 ), but no improvement in bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and pharmacological evaluation of nucleoside prodrugs designed to target siderophore biosynthesis in Mycobacterium tuberculosis

Dawadi

Kawamura

Rubenstein

et al. 2016

Bioorganic & Medicinal Chemistry

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The nucleoside antibiotic, 5′-O-[N-(salicyl)sulfamoyl]adenosine (1), possesses potent whole-cell activity against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). This compound is also active in vivo, but suffers from poor drug disposition properties that result in poor bioavailability and rapid clearance. The synthesis and evaluation of a systematic series of lipophilic ester prodrugs containing linear and α-branched alkanoyl groups from two to twelve carbons at the 3′-position of a 2′-fluorinated analogue of 1 is reported with the goal to improve oral bioavailability. The prodrugs were stable in simulated gastric fluid (pH 1.2) and under physiological conditions (pH 7.4). The prodrugs were also remarkably stable in mouse, rat, and human serum (relative serum stability: human~rat>>mouse) displaying a parabolic trend in the SAR with hydrolysis rates increasing with chain length up to eight carbons (t1/2 = 1.6 h for octanoyl prodrug 7 in mouse serum) and then decreasing again with higher chain lengths. The permeability of the prodrugs was also assessed in a Caco-2 cell transwell model. All of the prodrugs were found to have reduced permeation in the apical-to-basolateral direction and enhanced permeation in the basolateral-to-apical direction relative to the parent compound 2, resulting in efflux ratios 5–28 times greater than 2. Additionally, Caco-2 cells were found to hydrolyze the prodrugs with SAR mirroring the serum stability results and a preference for hydrolysis on the apical side. Taken together, these results suggest that the described prodrug strategy will lead to lower than expected oral bioavailability of 2 and highlight the contribution of intestinal esterases for prodrug hydrolysis.

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Pharmacokinetic and In Vivo Efficacy Studies of the Mycobactin Biosynthesis Inhibitor Salicyl-AMS in Mice

Cited by 48 publications

References 14 publications

Breaking a pathogen's iron will: Inhibiting siderophore production as an antimicrobial strategy

Breaking a pathogen's iron will: Inhibiting siderophore production as an antimicrobial strategy

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Synthesis and pharmacological evaluation of nucleoside prodrugs designed to target siderophore biosynthesis in Mycobacterium tuberculosis

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