Antibiotic adjuvants: an alternative approach to overcome multi-drug resistant Gram-negative bacteria

Antibiotic resistance in Gram-negative pathogens has emerged and constituted a global crisis, thereby novel antibiotics and other anti-infective strategies are urgently needed. However, the growing gap between clinical need and drug innovation, coupled with the membrane permeability barrier in Gram-negative bacteria restricts the discovery of Gram-negative antibiotics. Antibiotic adjuvants approach provides an alternative and complementary strategy for new antibiotic discovery. These compounds restore or potentiate the activity of commonly used antibiotics against multi-drug resistant (MDR) Gram-negative bacteria by targeting resistance or enhancing action of antibiotics. In this review, we first provide a brief overview of antibiotic resistance mechanism in Gram-negative bacteria, which can be used to guide the development of new antibiotic adjuvants. Additionally, we summarize the recent achievements in the search for antibiotic adjuvants based on their modes of action. Lastly, we discuss our perspectives in developing next-generation adjuvants such as broad-spectrum adjuvants and hybridization approach, which would contribute to enrich our arsenal against MDR Gram-negative bacteria.