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

Abstract

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.

C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration

“…Meanwhile, the nature of the substituent at C 9 does not seem to modulate the antibacterial activity significantly. Indeed, 9‐ t Bu‐DOX, which possesses both a tert ‐butyl group at C 9 and a dimethylamino group at C 4 , demonstrated higher MIC values than DOX (>200, 50, 6.25 μM against P. aeruginosa , E. coli , and S. aureus , respectively), [36] meaning that the substitution at C 9 may also decrease the antibacterial activity per se (Table 1).…”

Enhancing Inhibition of Both α-Synuclein Aggregation and Neuroinflammation: New Insights into the C-9 Modification of Doxycycline

“…On the other hand, the nature of the substituent at C9 does not seem to improve antibacterial activity. Indeed, 9-tBu-DOX, which possesses both the tert-butyl group at C9 and the dimethylamino group at C4, showed an increase of the MIC compared to DOX (>200, 50, 6.25 µM against P. aeruginosa, E. coli, and S. aureus, respectively), 30 meaning that the substitution at C9 also decreases the antibacterial activity (Table 1).…”