Treatment of human challenge and MDR strains of Neisseria gonorrhoeae with LpxC inhibitors.

Abstract

Objectives:

Inhibitors of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), which catalyses the second step in the biosynthesis of lipid A, have been developed as potential antibiotics for Gram-negative infections. Our objectives were to determine the effect of LpxC inhibition on the in vitro survival and inflammatory potential of Neisseria gonorrhoeae.

Methods:

Survival of four human challenge strains was determined after treatment with two LpxC inhibitors for 2 and 4 h. To confirm results from treatment and assess their anti-inflammatory effect, the expression of TNF-α by human THP-1 monocytic cells infected with bacteria in the presence of the LpxC inhibitors was quantified. Cytotoxicity of inhibitors for THP-1 cells was evaluated by release of lactate dehydrogenase. Survival of five MDR strains was determined after 2 h of treatment with an LpxC inhibitor and the effect of co-treatment on MICs of ceftriaxone and azithromycin was examined.

Results:

The inhibitors had bactericidal activity against the four human challenge and five MDR strains with one compound exhibiting complete killing at ≥5 mg/L after either 2 or 4 h of treatment. Treatment of gonococci infecting THP-1 monocytic cells reduced the levels of TNF-α probably owing to reduced numbers of bacteria and a lower level of expression of lipooligosaccharide. Neither inhibitor exhibited cytotoxicity for THP-1 cells. The MIC of azithromycin was slightly lowered by sublethal treatment of two MDR strains with an LpxC inhibitor.

Conclusions:

Our in vitro results demonstrated promising efficacy of LpxC inhibition of N. gonorrhoeae that warrants further investigation particularly owing to the rise in MDR gonorrhoea.

• Authors: Constance M John, Dongxiao Feng, Gary A Jarvis
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 73 Issue 8 Pg. 2064-2071 (08 01 2018) ISSN: 1460-2091 [Electronic] England
• PMID: 29726994 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Enzyme Inhibitors
• Tumor Necrosis Factor-alpha
• Amidohydrolases
• N-acetylglucosamine deacetylase

Topics

• Amidohydrolases (antagonists & inhibitors)
• Anti-Bacterial Agents (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Microbial Sensitivity Tests
• Molecular Structure
• Monocytes (cytology, microbiology)
• Neisseria gonorrhoeae (drug effects, enzymology)
• THP-1 Cells
• Tumor Necrosis Factor-alpha (immunology)