Scope and Limitations of Exploiting the Ability of the Chemosensitizer NV716 to Enhance the Activity of Tetracycline Derivatives against Pseudomonas aeruginosa.

Article

Author: Masi, Muriel ; Rose, Clémence ; Brunel, Jean-Michel ; Ferrié, Laurent ; Draveny, Margot ; Figadère, Bruno ; Pinet, Alexis

The spread of antibiotic resistance is an urgent threat to global health that requires new therapeutic approaches. Treatments for pathogenic Gram-negative bacteria are particularly challenging to identify due to the robust OM permeability barrier in these organisms. One strategy is to use antibiotic adjuvants, a class of drugs that have no significant antibacterial activity on their own but can act synergistically with certain antibiotics. Previous studies described the discovery and development of polyaminoisoprenyl molecules as antibiotic adjuvants with an OM effect. In particular, the compound NV716 has been shown to sensitize Pseudomonas aeruginosa to tetracycline antibiotics such as doxycycline. Here, we sought to explore the disruption of OM to sensitize P. aeruginosa to otherwise inactive antimicrobials using a series of tetracycline derivatives in the presence of NV716. We found that OM disruption expands the hydrophobicity threshold consistent with antibacterial activity to include hydrophobic molecules, thereby altering permeation rules in Gram-negative bacteria.

01 Aug 2022·European Journal of Medicinal Chemistry

The polyamino-isoprenyl potentiator NV716 revives disused antibiotics against Gram-negative bacteria in broth, infected monocytes, or biofilms, by disturbing the barrier effect of their outer membrane

Article

Author: Bolla, Jean-Michel ; Wang, Gang ; Rodriguez-Villalobos, Hector ; Van Bambeke, Françoise ; Brunel, Jean-Michel

Potentiators can improve antibiotic activity against difficult-to-treat Gram-negative bacteria like Escherichia coli, Klebsiella pneumoniae or Acinetobacter baumannii. They represent an appealing strategy in view of the paucity of therapeutic alternatives in case of multidrug resistance. Here, we examine the ability of the polyamino-isoprenyl compound NV716 to restore the activity of a series of disused antibiotics (rifampicin, azithromycin, linezolid, fusidic acid, novobiocin, chloramphenicol, and doxycycline, plus ciprofloxacin as an active drug) against these three species in planktonic cultures, but also in infected human monocytes and biofilms and we study its underlying mechanism of action. NV716 considerably reduced the MICs of these antibiotics (2-11 doubling dilutions), the highest synergy being observed with the more lipophilic drugs. This potentiation was related to a strong interaction of NV716 with LPS, ensuing permeabilization of the outer membrane, and leading to an increased accumulation of the antibiotics inside bacteria. Moreover, NV716 increased the relative potency of all drugs against intracellular infection by the same bacteria as well as their maximal efficacy, probably related to an improvement of antibiotic activity against persisters. Lastly, NV716 also enhanced rifampicin activity against biofilms from these three species. All these effects were observed at sub-MIC concentrations of NV716 (and thus unrelated to a bactericidal effect), and in conditions for which no toxicity was evidenced towards eukaryotic cells. Altogether, these data highlight for the first time the potential interest of NV716 as an adjuvant against these Gram-negative pathogens placed in the priority list of WHO for search of new therapies.

01 Apr 2021·International Journal of PharmaceuticsQ2 · MEDICINE

Feasibility of an inhaled antibiotic/adjuvant dry powder combination using an experimental design approach

Q2 · MEDICINE

Article

Author: Andrieu, Véronique ; Douafer, Hana ; Wafo, Emmanuel ; Brunel, Jean Michel ; Sergent, Michelle

The global increase of multidrug resistant bacteria and the lack of new classes of antibiotic especially those targeting Gram-negative pathogens are leaving the clinicians disarmed to treat numerous bacterial infections. Recently, the design of adjuvants able to enhance antibiotics activities appears to be one of the most promising investigated solutions to circumvent this problem. In this context, we have recently identified a new polyamino-isoprenyl derivative NV716 able to potentiate, at a very low concentration the activity of doxycycline against resistant P. aeruginosa bacterial strains by increasing its intracellular concentration. In this study we will report an experimental protocol to optimize a dry powder for inhalation ensuring the simultaneous delivery of an antibiotic (doxycycline) and an adjuvant (the polyaminoisoprenyl derivative NV716 since aerosol therapy could allow a rapid drug administration and target the respiratory system by avoiding the first pass effect and minimizing undesirable systemic effects. Thus, an experimental design was carried out permitting to identify the influence of several factors on the aerosolization efficiency of our combination and allowing us to find the right composition and manufacture leading to the best optimization of the simultaneous delivery of the two compounds in the form of an inhalable powder. More precisely, the powders of the two active ingredients were prepared by freeze drying and their aerosolization was improved by the addition of carrier particles of lactose inhalation grade. Under these conditions, the best formulation was defined by combining the optimal factors leading to the best aerodynamic properties' values (the lowest MMAD (Mass Median Aerodynamic Diameter) and the highest FPF (Fraction of Fine Particles)) without even using sophisticated engineering techniques. Finally, our results suggest that these molecules could be successfully delivered at the requested concentration in the lungs and then able to decrease drug consumption as well as increase treatment efficacy.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Negative Bacterial Infections	Preclinical	France	Université Catholique de Lille	01 Aug 2022

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