Nanomolar Inhibitors of Staphylococcus aureus Methionyl tRNA Synthetase with Potent Antibacterial Activity against Gram-Positive Pathogens

Jarvest, Richard L.; Berge, John M.; Berry, Valerie; Boyd, Helen; Brown, Murray J. B.; Elder, John S.; Forrest, Andrew K.; Fosberry, Andrew; Gentry, Daniel R.; Hibbs, Martin; Jaworski, Deborah D.; O’Hanlon, Peter J.; Pope, Andrew J.; Rittenhouse, Stephen; Sheppard, Robert J.; Slater-Radosti, Courtney; Worby, Angela

doi:10.1021/jm025502x

Cited by 97 publications

(69 citation statements)

References 14 publications

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“…One of the reasons for this failure was the inability of these lead compounds to cross the bacterial cell wall. A second reason was that the narrow spectrum of the antibactericidal activities of these lead compounds did not meet the requirement for further development (Fan et al , 2002; Jarvest et al , 2002; Payne et al , 2002). The number of antibiotics approved by the FDA has steadily decreased in the last two decades, while the total number of new molecular entities has remained about the same (Figure 1A).…”

Section: Discovery and Development Of New Antibiotics – Issues And Nementioning

confidence: 99%

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Zheng

Sun

Simeonov

2017

British J Pharmacology

222

200

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Infectious diseases account for nearly one fifth of the worldwide death toll every year. The continuous increase of drug‐resistant pathogens is a big challenge for treatment of infectious diseases. In addition, outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug‐resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared with previous decades. In parallel with this, is an increase in the number of drug‐resistant bacteria. For these threats and challenges to be countered, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combinations using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutic agents such as narrow spectrum antibiotics against drug‐resistant bacteria for these global challenges.Linked ArticlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc

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Section: Discovery and Development Of New Antibiotics – Issues And Nementioning

confidence: 99%

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Zheng

Sun

Simeonov

2017

British J Pharmacology

222

200

View full text Add to dashboard Cite

show abstract

“…5, structure 15) selectively inhibited bacterial MetRS (IC 50 ϭ 12 nM for S. aureus MetRS) and was potent against S. aureus (MIC ϭ 0.12 g/ml) and Enterococcus spp. (MIC ϭ 0.06 g/ml) (38,50). This compound was also efficacious in a groin abscess S. aureus infection model in rats (50).…”

Section: Synthetic and Semisynthetic Trna Synthetase Inhibitorsmentioning

confidence: 88%

“…(MIC ϭ 0.06 g/ml) (38,50). This compound was also efficacious in a groin abscess S. aureus infection model in rats (50). Similar to the classical AaRS inhibitor, mupirocin, compound 15 ( Fig.…”

Section: Synthetic and Semisynthetic Trna Synthetase Inhibitorsmentioning

confidence: 91%

Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Hurdle

O’Neill

Chopra

2005

Antimicrob Agents Chemother

191

172

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“…This pathogen has been recognized as largely responsible for both minor and serious to even life threatening acute and chronic infections, including atopic dermatitis, boils, bloodstream infections, central nervous system infections, toxic shock syndrome, pericarditis, endocarditis, pneumonia and osteomyelitis [24][25][26][27][28][29][30][31] . Also opportunistic H. parainfluenzae, under favorable conditions, may be the etiologic agents of various and unspecified infections, including those associated with biofilm formation [32][33][34] .…”

Section: Antibacterial Screening Against Clinical Isolates Of Mssa Anmentioning

confidence: 99%

Design, synthesis and biological evaluation of 4-benzoyl-1-dichlorobenzoylthiosemicarbazides as potent Gram-positive antibacterial agents

Paneth¹,

Plech²,

Kaproń³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Twelve 4-benzoyl-1-dichlorobenzoylthiosemicarbazides have been tested as potential antibacterials. All the compounds had MICs between 0.49 and 15.63 mg/ml toward Micrococcus luteus, Bacillus cereus, Bacillus subtilis and Staphylococcus epidermidis indicating, in most cases, equipotent or even more effective action than cefuroxime. In order to clarify if the observed antibacterial effects are universal, further research were undertaken to test inhibitory potency of two most potent compounds 3 and 11 on clinical isolates of Staphylococcus aureus. Compound 11 inhibited the growth of methicillin-sensitive S. aureus (MSSA) at MICs of 1.95-7.81 mg/ml, methicillin-resistant S. aureus (MRSA) at MICs of 0.49-1.95 mg/ml and MDR-MRSA at MIC of 0.98 and 3.90 mg/ml, respectively. Finally, inhibitory efficacy of 3 and 11 on planktonic cells and biofilms formation in clinical isolates of S. aureus and Haemophilus parainfluenzae was tested. The majority of cells in biofilm populations of MSSA and MRSA were eradicated at low level of 3, with MBICs in the range of 7.82-15.63 mg/ml.

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Nanomolar Inhibitors of Staphylococcus aureus Methionyl tRNA Synthetase with Potent Antibacterial Activity against Gram-Positive Pathogens

Cited by 97 publications

References 14 publications

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Design, synthesis and biological evaluation of 4-benzoyl-1-dichlorobenzoylthiosemicarbazides as potent Gram-positive antibacterial agents

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