Reversing resistance to counter antimicrobial resistance in the World Health Organisation's critical priority of most dangerous pathogens

Abstract

The speed at which bacteria develop antimicrobial resistance far outpace drug discovery and development efforts resulting in untreatable infections. The World Health Organisation recently released a list of pathogens in urgent need for the development of new antimicrobials. The organisms that are listed as the most critical priority are all Gram-negative bacteria resistant to the carbapenem class of antibiotics. Carbapenem resistance in these organisms is typified by intrinsic resistance due to the expression of antibiotic efflux pumps and the permeability barrier presented by the outer membrane, as well as by acquired resistance due to the acquisition of enzymes able to degrade β-lactam antibiotics. In this perspective article we argue the case for reversing resistance by targeting these resistance mechanisms - to increase our arsenal of available antibiotics and drastically reduce antibiotic discovery times - as the most effective way to combat antimicrobial resistance in these high priority pathogens.

Keywords: antibiotic resistance; antibiotics; efflux pump inhibitor; membrane permeability; reversal of resistance; synergism.

Figure 1. The list of the most dangerous pathogens in need of antimicrobial drug development according to the WHO [1]

Figure 2. Antimicrobial resistance mechanisms in Gram-negative bacteria and ways to reverse resistance

The four main mechanisms of antibiotic resistance in Gram-negative organisms (blue boxes) are (i) antibiotic inactivation, for example, the production of β-lactamase enzymes that hydrolyse the β-lactam ring thereby deactivating this class of antibiotics; (ii) target modification, for example modifications in the GyrA protein confers resistance to fluoroquinolones; (iii) active efflux, where drug efflux pumps remove the antibiotic from the bacterial cell thereby lowering antibiotic concentration to sub-toxic levels and (iv) prevention of drug entry through the OM by the expression of more selective porins, mutations in porins or loss of porins. Antibiotic resistance can be reversed by the addition of resistance breakers (orange boxes) such as (i) β-lactamase inhibitors to prevent antibiotic degradation; (ii) efflux pump inhibitors to allow the antibiotic to reach its target instead of being removed by the efflux pump; (iii-a) OM permeabilisers that destabilise the bacterial cell, thereby allowing antibiotics entry through the normally impenetrable OM; (iii-b) siderophore-drug conjugates which allow the antibiotic to breach the OM barrier by being transported through the siderophore specific porin and (iv) gene-silencing techniques to prevent expression of resistance determinants.