Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase

Hu, Qinghua; Liu, Ru-Juan; Fang, Zhipeng; Zhang, Jiong; Ding, Yingying; Tan, Min; Wang, Meng; Pan, Wei; Zhou, Huchen; Wang, En‐Duo

doi:10.1038/srep02475

Cited by 70 publications

(61 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The highly electrophilic nature of the boron component of these compounds leads to interaction with a variety of protein targets via reversible covalent bonds (8,9), with identified targets including leucyl-tRNA synthetase (LeuRS) (5,6) and ␤-lactamase (10). In particular, the benzoxaboroles tavaborole and AN3018 (6) inhibit fungal LeuRS, and AN3365 and AN3664/ZCL039 inhibit bacterial LeuRS (4,5).…”

mentioning

confidence: 99%

“…Benzoxaboroles are boron-containing compounds that have demonstrated potent activity against a number of infectious pathogens, including bacteria (4,5), fungi (6), and trypanosomes (7). The highly electrophilic nature of the boron component of these compounds leads to interaction with a variety of protein targets via reversible covalent bonds (8,9), with identified targets including leucyl-tRNA synthetase (LeuRS) (5,6) and ␤-lactamase (10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Sonoiki

Palencia

Guo

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum. Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC 50 ] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED 90 ], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [ 14 C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Sonoiki

Palencia

Guo

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…At this stage, however, CANBEF derivatives may prove useful in the treatment of fungal skin infections or as plant fungicides, where the issue of bioavailability does not arise. For example, the antifungal tavaborole, an inhibitor of aminoacyl-tRNA synthetase and protein synthesis, was recently authorized as an effective topical treatment for fungal nail infections (onychomycosis) (30).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis

Mircus

Albert

Ben-Yaakov

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cInvasive mycotic infections have become more common during recent decades, posing an increasing threat to public health. However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory and are limited to a small number of antifungals. The aim of this study was to identify novel fungal cell wall inhibitors from a library of small chemical compounds using a conditional protein kinase C (PKC)-expressing strain of Aspergillus nidulans sensitive to cell wall-active agents. Eight "hit" compounds affecting cell wall integrity were identified from a screen of 35,000 small chemical compounds. Five shared a common basic molecular structure of 4-chloro-6-arylamino-7-nitro-benzofurazane (CANBEF). The most potent compound, CANBEF-24, was characterized further and was shown to inhibit the growth of pathogenic Aspergillus, Candida, Fusarium, and Rhizopus isolates at micromolar concentrations but not to affect the growth of mammalian cell lines. CANBEF-24 demonstrated strong synergy in combination with caspofungin, an antifungal that inhibits cell wall biosynthesis. Genetic and biochemical analyses with Aspergillus nidulans and Saccharomyces cerevisiae indicated that CANBEFs selectively inhibit fungal rRNA maturation and protein synthesis, suggesting that their effect on the cell wall is indirect. CANBEFs were nontoxic in insect (Galleria mellonella, Drosophila melanogaster) and mouse models of fungal infection. Preliminary evidence showing no therapeutic benefit in these models suggests that further cycles of optimization are needed for the development of this novel class of compounds for systemic use.T he number of life-threatening invasive fungal infections has risen dramatically over the past 30 years (1, 2). The vast majority of these infections are caused by species of the genera Candida, Aspergillus, Cryptococcus, and Coccidioides (3). Invasive aspergillosis has now overtaken candidiasis as the most frequent invasive fungal infection found after death in Europe and the United States (4, 5). Today, as many as 4% of all patients dying in modern tertiary care hospitals have invasive aspergillosis caused by fungal pathogen species that belong to the genus Aspergillus, while as many as 2% of these patients suffer from invasive candidiasis caused by Candida species (4, 6). However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory.There are three main classes of antifungal drugs in common clinical use for the treatment of systemic mycoses: the polyene amphotericin B, which binds fungal membrane ergosterol, leading to cell lysis; azoles, which inhibit ergosterol biosynthesis (fluconazole, itraconazole, voriconazole [VRC], and posaconazole); and the newly introduced echinocandins, such as caspofungin (CAS), which inhibit fungal glucan biosynthesis. Most of these current systemic antifungal treatments interact unfavorably with other medications, have resistance problems, a narrow spectrum of activity, and limited formulations, and are fungistatic rather...

show abstract

“…A promising new class of compounds that could be of specific interest to the pediatric field are the oxaborole-based leucyl-tRNA synthetase (LeuRS) inhibitors being pursued by Anacor [171]. Other tRNA synthetases have been the subject of antimicrobial investigation [172] and have displayed promise as a novel class of antitubercular agents.…”

Section: New Drugsmentioning

confidence: 99%

Advances in Drug Discovery and Development for Pediatric Tuberculosis

Hoagland¹,

Zhao²,

Lee

2016

MRMC

View full text Add to dashboard Cite

Pediatric tuberculosis is an underappreciated global epidemic estimated to afflict around half a million children worldwide. This problem has historically been overlooked, due in part to their low social status and the difficulty in diagnosis of tuberculosis in children. Children are more susceptible to tuberculosis infection and disease progression, including rapid dissemination into extra-pulmonary infection sites. Treatment of pediatric tuberculosis infections has been traditionally built around agents used to treat the adult disease, but the disease pathology, drug pharmacokinetics and the safety window in children differs from the adult disease. This produces additional concerns for drug discovery and development of new agents. This review examines: (i) the safety concerns for current front and second line agents used to treat complex drug resistant infections and how this knowledge can be used to identify, prioritize and dose agents that may be better tolerated in pediatric populations; (ii) the chemistry and suitability of new drugs in the clinical development pipeline for tuberculosis for the treatment of pediatric infections indicating several new agents may offer significant improvements for the treatment of multi-drug resistant tuberculosis in children.

show abstract

Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase

Cited by 70 publications

References 42 publications

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis

Advances in Drug Discovery and Development for Pediatric Tuberculosis

Contact Info

Product

Resources

About