Novel inhibitors of NorA efflux pump for combating antimicrobial resistance

Problem addressed

Antimicrobial resistance (AMR) is a leading cause of death worldwide and has been identified by the World Health Organisation (WHO) as one of largest threats facing global health and development. The development of inhibitors of resistance mechanisms would allow the use of existing drugs in combination therapy as a method of targeting resistant bacteria.

Proposed solution

Efflux pumps represent the first-line mechanism of resistance for many bacteria, whereupon extrusion of the drug reduces the intracellular concentration below the level of therapeutic efficacy. Inhibition of  the protein NorA would prevent the efflux of antibiotics such as ciprofloxacin, increasing their efficacy and hence reducing the emergence of resistance. Use of these novel compounds of NorA inhibitors may be used to resensitise bacteria to fluoroquinolone antibiotics or  as a combination therapy with a fluoroquinolone antibiotic to treat a bacterial infection.

Technology overview

This invention identifies novel compounds to tackle antimicrobial resistance (AMR). Through a novel high-throughput phenotypic screen, the researchers have identified the first potent and druglike inhibitors of the Staphylococcus aureus (S. aureus) NorA multidrug efflux pump, a key driver of clinical resistance to antibiotics such as ciprofloxacin. The inventors have developed novel compounds to provide a potent in vivo tool to validate NorA as a therapeutic target in murine bacteraemia models, and subsequently establish a chemical series suitable for future development for combination therapy with existing antibiotics. The inventors  have further established compounds with potent activity in vitro models.

Figure 1

Benefits

• Treatment of bacterial infections.
• Can prevent the emergence of resistant strains.
• Exhibit superior potency and low toxicity over other NorA inhibitors.
• Potent inhibitors that re-sensitised methicillin-resistant S. aureus (MRSA) to the antibiotic ciprofloxacin.
• Validates NorA as a therapeutic target and establishes a chemical series suitable for future development for combination therapy with existing antibiotics.

Intellectual property information

NorA inhibitors is protected by UK patent application: GB2319181.0