Effect of coevolution between bacterial host and beta-lactamase-producing plasmid on the spread of beta-lactams resistance

Background

Antibiotic resistance increases the cost of health care and causes therapy failure. It is estimated that antimicrobial resistance could be responsible for 10 million deaths per year globally by 2050. Beta-lactam antibiotics are one of the most widely used relevant drug classes of antibacterial agents. They include penicillins, cephalosporins, carbapenems, penems (also known as thiopenems) and monobactams. Beta-lactam resistance of gram-negative bacteria results mainly from the interplay between four factors: (i) the sensitivity of the target (i.e., the penicillin-binding proteins, PBPs), (ii) the catalytic activity and concentration of the periplasmic beta-lactamases, (iii) the permeability of the outer membrane and (iv) the expression and affinity of the efflux system. Hydrolysis of beta-lactams by beta-lactamases is the most common resistance mechanism to this drug class. AmpC, the gene encoding AmpC-type beta-lactamase, is often encoded by conjugative plasmids that may transfer horizontally. Similarly, blaKPC, blaFOX, and blaTEM-1, which confer resistance to carbapenems, cephalosporins, penicillins and early cephalosporins, respectively, are plasmid-encoded and the KPC carbapenemases are associated with outbreaks in hospitals and increasingly spread worldwide.  

Bacterial hosts of beta-lactamase-producing plasmids (BLP plasmids) are potential reservoirs of these antibiotic resistant genes, by transferring these genes to non-resistant strains. Previous studies have identified at least five human-originated E. coli strains harbouring plasmids with blaCTX-M-14 (encoding an extended-spectrum beta-lactamase, ESBL) that are self-transmissible, and are able to transfer to E. coli DH10B using liquid mating assays. However, the spread of BLP plasmids does not only depend on a fixed rate at which they are transferred to new host bacteria, but also on the growth rate of donor and recipient bacteria and on the stability of plasmid carriage. All these parameters are potentially subject to changes caused by the coevolution of host and plasmid. Yet, little is known about how host-plasmid coevolution affects the spread of BLP plasmids by affecting host fitness or transfer rates, nor about the specific molecular mechanisms involved in plasmid-host coevolution. 

It is therefore important to better understand the dynamics and mechanisms of coevolution of bacterial host and conjugative BLP plasmids, and their effect on conjugation efficiencies, host range, fitness and evolvability of beta-lactams-resistance. 

Project description

Our study focuses on a better fundamental understanding of the possible role of rapid coevolution of BLP plasmids and bacterial hosts in the success and spread of antibiotic resistance. Addressing this current knowledge gap is important and may contribute to gain knowledge on molecular mechanisms of BLP-plasmid-host coevolution, and its effect on beta-lactamase gene spreading, which in a much later stage may lead to changes in antimicrobial usage and developing new therapies for the control of beta-lactams resistance.