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Method for increasing the susceptibility of peptide deformylase inhibitors by using efflux pump inhibitors

A kind of efflux pump inhibitor, efflux pump technology, applied in the field of peptidyl deformylase (peptidyl deformylase) inhibitor

Inactive Publication Date: 2007-06-06
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the main potential barriers to the development of these new agents are those general mechanisms responsible for intrinsic resistance to a wide range of structurally unrelated compounds

Method used

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  • Method for increasing the susceptibility of peptide deformylase inhibitors by using efflux pump inhibitors
  • Method for increasing the susceptibility of peptide deformylase inhibitors by using efflux pump inhibitors
  • Method for increasing the susceptibility of peptide deformylase inhibitors by using efflux pump inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212] The role of acrAB pump in reducing the intrinsic sensitivity to LBM415

[0213] The insertion inactivation of acrB in the laboratory strain NB65044 (see Figure 1) significantly increased the sensitivity to LBM415, which showed that the MIC of LBM415 decreased from 4μg / mL for the parent strain to the acrB-deficient derivative NB65044 -CDS0001 is 0.25μg / mL. See Table 2 below. The insertion also increased the sensitivity to LBK611 and the known pump substrate erythromycin [see Sanchez, Pan, Vinas, and Nikaido (1997), supra], and more significantly increased the sensitivity to another macrolide ( Clindamycin), but did not significantly affect the sensitivity of the pump's non-substrate tetracycline [see Sanchez, Pan, Vinas and Nikaido (1997), see above]. See Table 2. The non-substrate chloramphenicol of another known pump was also not affected by the loss of acrB (data not shown). This proves that the Haemophilus influenzae AcrAB pump is the main driver of the reduced sensitivi...

Embodiment 2

[0222] Identification of the outer membrane components of acrAB homologous efflux pump

[0223] It has been proved that the acrAB pump is the main contributor to the intrinsic resistance to PDF inhibitors and macrolides in Haemophilus influenzae. It is of interest to identify the components of the outer membrane channel of the pump to complete the three-layer structure of the pump (Tripartire architecture). The protein homology search of the Haemophilus influenzae genome using the TolC outer membrane channel, the partner of acrAB in E. coli, showed that it was significantly similar to ORFHI1462 (expected value 2.9×10 -6 ). Interestingly, the oprM component of the mexAB-oprM pump of Pseudomonas aeruginosa produces a closer match with HI1462, and its expected value is 2.8×10 -22 This shows that HI1462 is a good candidate for the outer membrane channel. Consistent with this, the inactivation of HI1462 in Haemophilus influenzae NB65044 (see Figure 1) increased the sensitivity to eryth...

Embodiment 3

[0226] acrAB and reduced sensitivity to PDF inhibitors in clinical strains of Haemophilus influenzae

[0227] The reduced sensitivity to antibiotics in some clinical isolates of bacteria is related to the overexpression of the efflux pump. Historically, the identification of repressor mutations and / or overexpression of pump genes in clinical isolates has been sufficient to attribute reduced resistance to efflux, which may be the usual case, but in repressor gene mutations and / or Or there is not always a clear correlation between the expression status of the pump and resistance to specific antibiotics. See Sobel, McKay and Poole, Antimicrob Agents Chemother, Volume 47, No. 10, pp. 3202-3207 (2003). Therefore, in order to directly explain whether the acrAB pump plays an important role in mediating reduced sensitivity in those clinical strains with the lowest sensitivity to PDF inhibitors, it was killed in strains NB65016, NB65027, NB65051, NB65063, NB65069 and NB65076. With live acr...

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Abstract

The present invention provides methods and compositions for increasing the susceptibility of PDF inhibitors against Gram-negative organisms by using efflux pump inhibitors.

Description

Field of invention: [0001] The present invention relates to a peptidyl deformylase (PDF) inhibitor, and particularly relates to a method for enhancing the efficacy of a PDF inhibitor against Gram-negative bacteria by using an efflux pump inhibitor. Background of the invention: [0002] The continued emergence and expansion of target-based resistance to existing antibiotic substances has made it clear that there is a need for compound modifications aimed at preventing these mechanisms, or, better still, the need to discover compounds that target new cell functions, for which cell functions are undesirable. Pre-existing target-based resistance confers cross-resistance. A new class of hydroxylamine compounds that inhibit the undeveloped function of PDF has shown great promise in this regard, especially against Gram-positive bacteria, including those with well-defined resistance mechanisms to commonly used antibiotics. Positive bacteria. See WO 02 / 102790A1. PDF is a metallopeptidase ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61K31/00A61K31/167A61P31/04
CPCA61K45/06A61K31/00A61K31/4439A61K31/167A61P31/04A61P43/00Y02A50/30A61K2300/00
Inventor C·R·德昂N·S·赖德
Owner NOVARTIS AG
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