Antimicrobial resistance has become a major problem worldwide resulting in high mortality and immense pressure on global healthcare. In this regard, Gram-negative bacteria constitute the most critical bacteria due to presence of ubiquitous and non-specific resistance elements like impermeable outer membrane and over-expression of efflux pumps. In view of this, there is a pertinent need to invest in novel therapeutic strategies to combat infections caused by Gram-negative superbugs. In this present study, we have come up with a non-traditional therapeutic approach comprising of antibiotic adjuvants. Thorough structure-activity relationship (SAR) studies revealed that cyclic hydrophobic groups, along with positive charges in small molecules result in weak interaction with the bacterial membrane leading to no activity against bacteria and no toxicity to mammalian cells. However, this weak membrane-perturbation comprising of slight outer-membrane permeabilization, and membrane depolarization was enough to potentiate multiple classes of obsolete antibiotics against clinical isolates of Gram-negative superbugs. Rifampicin, fusidic acid, tetracyclines, linezolid, vancomycin and other antibiotics were potentiated by a factor as high as 1024-times, in the best cases. Mechanism of potentiation was overcoming the permeability barrier and inhibition of efflux of antibiotics through weak perturbation of the bacterial membrane. The lead combination of adjuvant and antibiotic was effective in completely eradicating metabolically inactive stationary phase bacteria. The combination was also able to reduce the bacterial burden in difficult-to-treat mixed species biofilms of <i>P. aeruginosa </i>and methicillin resistant <i>S. aureus</i> (MRSA) by 1.5-2.5 log. The viability of dispersed cells was also reduced by 4-8 log. In conclusion, this report describes a weak membrane-perturbing small molecule which can be used as a generic antibiotic adjuvant and revitalize the efficacy of existing antibiotics against complicated forms of multidrug-resistant Gram-negative superbugs.

Small molecular adjuvants to rehabilitate and repurpose multiple classes of antibiotics against gram-negative superbugs

ACS Spring 2022

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