During the last decades, multiple approaches have been developed to combat bacterial resistance.However, the combination of antibiotic resistance mechanisms by bacteria and the limited number of effective antibiotics available, decreases the number of the interventions for the treatment of current bacterial infections. The solution to emerging antibiotic resistance will likely involve combination therapies of existing antibiotics and smart adjuvants, which re-empower the antibiotic agent to become efficacious against the resistant strain of interest. In this context, amphiphatic molecules provide the opportunity to target difficult-to-traverse bacterial membranes. We will depict herein that a reasoned adjuvant design permits to perform polypharmacy on bacteria by not only providing greater internal access to the co-dosed antibiotics but also by de-energizing the efflux pumps used by the bacteria to escape antibiotic action.
The rise of antimicrobial resistance has created an urgent need for the development of new methods for antibiotics delivery to patients with pulmonary infections in order to mainly increase the effectiveness of the drugs administration, to minimize the risk of emergence of resistant strains, and to prevent patients reinfection. Since bacterial resistance is often related to antibiotic concentration, their pulmonary administration could eradicate strains resistant to the same drug at the concentration achieved through the systemic circulation. Pulmonary administration offers several advantages; it directly targets the site of the infection which allows the inhaled dose of the drug to be reduced compared to that administered orally or parenterally while keeping the same local effect. The review article is made with an objective to compile information about various existing modern technologies developed to provide greater patient compliance and reduce the undesirable side effect of the drugs. In conclusion, aerosol antibiotic delivery appears as one of the best technologies for the treatment of pulmonary infectious diseases and able to limit the systemic adverse effects related to the high drug dose and to make life easier for the patients.
The discovery of new antibiotic adjuvants is an attractive option for overcoming antimicrobial resistance. We have previously reported the discovery of a bis‐6‐bromoindolglyoxylamide derivative of spermine as being able to enhance the action of antibiotics against Gram‐negative bacteria but suffers from being cytotoxic and red‐blood cell haemolytic. A series of analogues was prepared exploring variation of the indolglyoxylamide unit, to include indole‐3‐acrylic, indole‐3‐acetic and indole‐3‐carboxylate units, and evaluated for antibiotic enhancing properties against a range of Gram‐negative bacteria, and for intrinsic antimicrobial, cytotoxic and haemolytic properties. Two spermine derivatives, bearing 5‐bromo‐indole‐3‐acetic acid (17) and 5‐methoxy‐indole‐3‐acrylic acid (14) end groups were found to exhibit good to moderate antibiotic adjuvant activities for doxycycline towards the Gram‐negative bacteria Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, but with more modest intrinsic antimicrobial activity and greatly reduced cytotoxic and haemolytic properties. The mechanism of action of the latter derivative identified its ability to disrupt the outer membranes of bacteria and to inhibit the AcrAB‐TolC efflux pump directly or by inhibiting the proton gradient.
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