Fitness Cost of blaNDM-5-Carrying p3R-IncX3 Plasmids in Wild-Type NDM-Free Enterobacteriaceae

Abstract

The wide dissemination of New Delhi metallo-β-lactamase genes (blaNDM) has resulted in the treatment failure of most available β-lactam antibiotics, with IncX3-type blaNDM-5-carrying plasmids recognised as having spread worldwide. In China, bacteria carrying these plasmids are increasingly being detected from diverse samples, including hospitals, communities, livestock and poultry, and the environment, suggesting that IncX3 plasmids are becoming a vital vehicle for blaNDM dissemination. To elucidate the fitness cost of these plasmids on the bacterial host, we collected blaNDM-negative strains from different sources and tested their ability to acquire the blaNDM-5-harboring p3R-IncX3 plasmid. We then measured changes in antimicrobial susceptibility, growth kinetics, and biofilm formation following plasmid acquisition. Overall, 70.7% (29/41) of our Enterobacteriaceae recipients successfully acquired the blaNDM-5-harboring p3R-IncX3 plasmid. Contrary to previous plasmid burden theory, 75.9% (22/29) of the transconjugates showed little fitness cost as a result of plasmid acquisition, with 6.9% (2/29) of strains exhibiting enhanced growth compared with their respective wild-type strains. Following plasmid acquisition, all transconjugates demonstrated resistance to most β-lactams, while several strains showed enhanced biofilm formation, further complicating treatment and prevention measures. Moreover, the highly virulent Escherichia coli sequence type 131 strain that already harbored mcr-1 also demonstrated the ability to acquire the blaNDM-5-carrying p3R-IncX3 plasmid, resulting in further limited therapeutic options. This low fitness cost may partly explain the rapid global dissemination of blaNDM-5-harboring IncX3 plasmids. Our study highlights the growing threat of IncX3 plasmids in spreading blaNDM-5.

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

“…10,20 The rapid spread of bla NDM may in part be due to the limited fitness cost conferred by this enzyme to its bacterial hosts. 21,22 Among MBL enzymes NDM is the most common in Enterobacterales; a study conducted using isolates from 40 countries between 2012 and 2014 revealed that 44.2% of all MBL-producing Enterobacterales possessed bla NDM , 39.3% harbored bla VIM , and 16.5% contained bla IMP . 11 K. pneumoniae, followed by E. coli, are the most common hosts of bla NDM across global surveillance studies.…”

Characterization of an NDM-5-producing hypervirulent Klebsiella pneumoniae sequence type 65 clone from a lung transplant recipient

“…In the absence of antibiotic pressure, the presence of resistance genes in plasmids will impose fitness costs on their host [ 12 ]. However, a recent in vitro study has shown that up to 75.9% (22/29) Enterobacteriaceae strains did not produce fitness costs after obtaining the IncX3 plasmid through conjugation test [ 13 ], which may facilitate the dissemination of the plasmid. Genomic islands are clusters of genes of probable horizontal origin in bacterial or archaeal genomes.…”

Piggybacking on niche-adaptation reduces the cost of multidrug resistance plasmids

“…On a broader perspective, our results warrant further research on plasmid-evolutionary dynamics in different E. coli lineages and sub-lineages to better understand why some of them appear to be more prone to acquire and maintain MDR plasmids [6, 47]. Available data support that plasmids of clinical origins rarely reduce fitness of clinical host strains [29, 30, 45, 49–51] to the extent often seen in the pioneering studies of plasmid-host compensatory evolution [10, 20, 22, 52]. It is also clear that this alone cannot explain how successful clone-plasmid associations emerge.…”