A Biological Approach to Antimicrobial Resistance in New and Old Bacterial Pathogens

Resistance to antimicrobials in bacterial pathogens has become a major global public health issue that international institutions are now realizing must be tackled with a degree of urgency. A major issue is the self-transmissibility of the plasmids that carry most of the resistance genes. Scientists are now exploring ways in which the antimicrobial resistance plasmids might be tackled directly to reduce resistance. Pharmacological approaches to destabilizing plasmids have not yet been tested in vivo. Phagemids may be used to introduce genes which harm the bacteria themselves or disrupt key plasmid genes. The transfer of transmissible plasmids is mediated by thin conjugative pili which are also attachment sites for a range of lytic bacteriophages. Such phages may be used to kill bacterial cultures where fimbriae are highly de-repressed. They also select for the small number of bacterial cells which have spontaneously lost their plasmid, thereby replacing an antibiotic-resistant strain with one which is once again fully susceptible to antibiotics. This has been demonstrated both in vitro and in animal models of infection. A pharmaceutical approach is proposed to de-repress the plasmids possessed by many strains and thereby increase phage susceptibility.