Resistance to second-line drugs in multidrug-resistant tuberculosis – Authors' reply

Dalton, Tracy; Cegielski, Peter; Kurbatova, Ekaterina V.; Ershova, Julia; Caoili, Janice Campos

doi:10.1016/s0140-6736(13)60343-8

Cited by 1 publication

(2 citation statements)

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“…These multidrug‐resistant (MDR) Mtb strains require treatment with second‐line drugs, which are less potent, have more side effects,4 and are more expensive 3. Misuse of second‐line treatments has been linked to the emergence of extensively drug‐resistant (XDR) Mtb strains 5. Unfortunately, the second‐line TB treatments are used to treat other bacterial infections, and this makes it impractical to restrict them to TB treatment in order to minimise their misuse 5.…”

Section: Introductionmentioning

confidence: 99%

“…Misuse of second‐line treatments has been linked to the emergence of extensively drug‐resistant (XDR) Mtb strains 5. Unfortunately, the second‐line TB treatments are used to treat other bacterial infections, and this makes it impractical to restrict them to TB treatment in order to minimise their misuse 5. Thus, there is a great need to develop new classes of anti‐TB agents that have new modes of action.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing the Chemical Scaffold of the Anti‐Arthritic Drug Lobenzarit to Target Tryptophan Biosynthesis in Mycobacterium tuberculosis

et al. 2014

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The emergence of extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) highlights the need for new therapeutics to treat tuberculosis. We are attempting to fast-track a targeted approach to drug design by generating analogues of a validated hit from molecular library screening that shares its chemical scaffold with a current therapeutic, the anti-arthritic drug Lobenzarit (LBZ). Our target, anthranilate phosphoribosyltransferase (AnPRT), is an enzyme from the tryptophan biosynthetic pathway in Mtb. A bifurcated hydrogen bond was found to be a key feature of the LBZ-like chemical scaffold and critical for enzyme inhibition. We have determined crystal structures of compounds in complex with the enzyme that indicate that the bifurcated hydrogen bond assists in orientating compounds in the correct conformation to interact with key residues in the substrate-binding tunnel of Mtb-AnPRT. Characterising the inhibitory potency of the hit and its analogues in different ways proved useful, due to the multiple substrates and substrate binding sites of this enzyme. Binding in a site other than the catalytic site was found to be associated with partial inhibition. An analogue, 2-(2-5-methylcarboxyphenylamino)-3-methylbenzoic acid, that bound at the catalytic site and caused complete, rather than partial, inhibition of enzyme activity was found. Therefore, we designed and synthesised an extended version of the scaffold on the basis of this observation. The resultant compound, 2,6-bis-(2-carboxyphenylamino)benzoate, is a 40-fold more potent inhibitor of the enzyme than the original hit and provides direction for further structure-based drug design.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%