当前位置： SCI文献检索 > ANTIMICROBIAL AGENTS AND CHEMOTHERAPY期刊下所有文献 > The polyaminoisoprenyl potentiator NV716 revives old disused antibiotics against intracellular forms of infection by Pseudomonas aeruginosa.

The polyaminoisoprenyl potentiator NV716 revives old disused antibiotics against intracellular forms of infection by Pseudomonas aeruginosa.

Abstract：

:Active efflux confers intrinsic resistance to multiple antibiotics in Pseudomonas aeruginosa, including old disused molecules. Beside resistance, intracellular survival is another reason for failure to eradicate bacteria with antibiotics. We evaluated the capacity of polyaminoisoprenyl potentiators (designed as efflux pump inhibitors [EPIs]) NV716 and NV731 compared to PAβN to restore the activity of disused antibiotics (doxycycline, chloramphenicol [substrates for efflux], rifampin [not substrate]) in comparison with ciprofloxacin against intracellular P. aeruginosa (strains with variable efflux levels) in THP-1 monocytes exposed during 24h to antibiotics alone (0.003-100x MIC) or combined with EPIs. Pharmacodynamic parameters (apparent static concentrations [Cs]; maximal relative efficacy [Emax]) were calculated using the Hill equation of concentration-response curves. PAβN and NV731 moderately reduced (0-4 doubling dilutions) antibiotic MICs but did not affect their intracellular activity. NV716 markedly reduced (1-16 doubling dilutions) the MIC of all antibiotics (substrates or not for efflux; strains expressing efflux or not); it improved their relative potency and maximal efficacy (lower Cs; more negative Emax) intracellularly. In parallel, NV716 reduced the persister fraction in stationary cultures when combined with ciprofloxacin. In contrast to PAβN and NV731 that act as EPIs against extracellular bacteria only, NV716 can resensitize P. aeruginosa to antibiotics whether substrates or not for efflux, both extracellularly and intracellularly. This suggests a complex mode of action that goes beyond a simple inhibition of efflux and reduces bacterial persistence. NV716 may appear as a useful adjuvant, including to disused antibiotics with low antipseudomonal activity, to improve their activity, including against intracellular P. aeruginosa.

journal_name

Antimicrob Agents Chemother

journal_title

Antimicrobial agents and chemotherapy

authors

Wang GW,Brunel JM,Bolla JM,Van Bambeke F

doi

10.1128/AAC.02028-20

subject

Has Abstract

pub_date

2020-12-14 00:00:00

eissn

0066-4804

issn

1098-6596

pii

AAC.02028-20

pub_type

杂志文章

在线工具

The polyaminoisoprenyl potentiator NV716 revives old disused antibiotics against intracellular forms of infection by Pseudomonas aeruginosa.