Synthesis of Small Molecule Disruptors of Bacterial Resistance Mechanisms

The continued emergence of multi-drug resistant (MDR) bacteria is a rising threat to global human health. With the discovery of plasmid borne resistance to colistin found in 2015, the possibility of bacterial strains with pan-antibiotic resistance became a reality. Due to financial issues, most large pharmaceutical companies have all but abandoned the development of new antibiotics, favoring research and development on treatments that can provide their shareholders greater returns on investment. Due to the lack of industrial interest, the challenges of developing new antibiotics and finding alternative approaches to fighting multi-drug resistant bacterial infections have fallen on small startup biopharmaceutical companies and academic research groups. Herein, two alternative strategies to developing novel broad-spectrum antibiotics will be discussed: antibiotic adjuvants and small molecule virulence inhibitors.

Antibiotic adjuvants are compounds that disrupt mechanisms of antibiotic resistance and can be administered with traditional antibiotics to provide a powerful combination treatment to combat MDR bacteria. One example of adjuvants are compounds

that can disrupt biofilms. Biofilms are highly organized surface associated communities encased within an extracellular polymeric substance (EPS) which can afford the bacteria up to 1000-fold increases in resistance to antibiotics. By either inhibiting biofilm formation or dispersing pre-formed biofilms, adjuvants can allow antibiotics to eradicate infections more effectively. Additionally, adjuvants that are capable of reversing colistin resistance offer the possibility of decreased antibiotic resistance evolution while also allowing physicians continued use of colistin as the antibiotic of last resort against MDR Gram- negative infections.

Small molecule virulence inhibitors are small molecules that are nontoxic to the bacteria but prevent the secretion of virulence factors. By selectively inhibiting nonessential signaling pathways such as two-component systems, virulence inhibitors can prevent increased incidence of resistance and weaken bacteria allowing the host’s immune system to clear infections without additional antibacterial agents.

This manuscript discusses the synthesis and testing of compounds that show antibiofilm activity against methicillin resistant Staphylococcus aureus (MRSA) and colistin potentiation against colistin resistant strains of Klebsiella pneumonia and Acinetobacter baumannii. Furthermore, two sets of compounds are presented that inhibit a global virulence signaling cascaded in S. aureus, one of which is also able to potentiate the ß-lactam oxacillin in MRSA.