Molecular mechanisms of antibiotic resistance

Blair, Jessica M A; Webber, Mark A.; Baylay, Alison J.; Ogbolu, David Olusoga; Piddock, Laura J. V.

doi:10.1038/nrmicro3380

Cited by 3,160 publications

(2,639 citation statements)

References 145 publications

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“…7 This is where the multichannel device, iChip, 8 has made a considerable contribution enabling the identification of molecules like teixobactin, some of which could be active against drug resistant bacteria. However, the iChip device has its limitations.…”

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Efficient total syntheses and biological activities of two teixobactin analogues

et al. 2016

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The discovery of the new antibiotic teixobactin has been timely in the race for unearthing novel antibiotics wherein the emergence of drug resistance bacteria poses a serious threat worldwide. Herein, we present the total syntheses and biological activities of two teixobactin analogues. This approach is simple, efficient and has several advantages: it uses commercially available building blocks (except AllocHN-D-Thr-OH), has a single purification step and a good recovery (22). By using this approach we have synthesised two teixobactin analogues and established that the D-amino acids are critical for the antimicrobial activity of these analogues. With continuing high expectations from teixobactin, this work can be regarded as a stepping stone towards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules

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Efficient total syntheses and biological activities of two teixobactin analogues

et al. 2016

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“…There are two differences between the enzymes that may be significant for inhibitor binding: (1) CcrA has a glycine at position 119, which is glutamine in NDM-1 and interacts with the hydroxyl group of 6c. With glycine, no such interaction is possible in CcrA.…”

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confidence: 99%

Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

Zhai

Zhang

Kang

et al. 2016

ACS Med. Chem. Lett.

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ABSTRACT:The metallo-β-lactamases (MβLs) cleave the β-lactam ring of β-lactam antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors of representatives of the three subclasses of MβLs. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC 50 value range of 0.15−1.90 μM, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 μM. Compounds 4d and 6c are partially mixed inhibitors with K i values of 0.49 and 0.63 μM using cefazolin as the substrate. Structure−activity relationship studies reveal that replacement of hydrogen on the aromatic ring by chlorine, heteroatoms, or alkyl groups can affect bioactivity, while leaving the aromatic ring of the triazolylthiols unmodified maintains the inhibitory potency. Docking studies reveal that the typical potent inhibitors of NDM-1, 4d and 6c, form stable interactions in the active site of NDM-1, with the triazole bridging Zn1 and Zn2, and the amide interacting with Lys 211 (Lys224).

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“…Overproduction of efflux pumps can occur via four mechanisms: (i) mutation of the local repressor gene (7,8), (ii) mutation in a global regulatory gene (9,10), (iii) mutation of the promoter region of the efflux pump gene (11), or (iv) insertion elements upstream of the transporter gene (12,13).…”

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AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

Blair

Bavro

Ricci

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre-and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrABTolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.efflux | antimicrobial resistance | AcrB | whole genome sequencing

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Molecular mechanisms of antibiotic resistance

Cited by 3,160 publications

References 145 publications

Efficient total syntheses and biological activities of two teixobactin analogues

Efficient total syntheses and biological activities of two teixobactin analogues

Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

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