Overcoming intrinsic resistance in Pseudomonas aeruginosa using non-ribosome targeting tobramycin-based adjuvants

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Challenges and strategies to overcome intrinsic resistance in Pseudomonas aeruginosa
Poor outer membrane permeability and overexpression of multidrug efflux pumps, the hallmarks of intrinsic resistance in Gram-negative bacteria (GNB), prevent many classes of antibiotics from achieving the required intracellular or periplasmic concentrations to elicit their antibacterial effect [1,2]. One problematic pathogen that uses intrinsic resistance at near perfection is Pseudomonas aeruginosa. P. aeruginosa expresses more than 30 selective or ‘slow’ porins, up to 12 multidrug efflux pumps, and different types of antibiotic-inactivating enzymes (e.g., b-lactamases, aminoglycoside-modifying enzymes and others) that concertedly reduce the concentrations of antibiotics in the cell [3].

One strategy to enhance the outer membrane uptake of antibacterials into GNB uses the ‘Trojan horse’ strategy to trick bacteria into taking up antibiotics by ligation of moieties that are normally used to transport nutrients or iron-chelating siderophores into the bacterial cell [4]. This approach increases the molecular weight of the parent antibiotic, an attribute often comprehended to reduce the drug likeness of molecules. For instance, the minimal inhibitory concentration (MIC) of cefiderocol, an iron-chelating catechol-conjugated cephalosporin in Phase III clinical trials, is > 64-fold reduced against multi-drug resistant (MDR) P. aeruginosa isolates at iron deficient conditions believed to mimic physiological conditions [5].

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