Abstract
Klebsiella pneumoniae, an Enterobacteriaceae that mostly causes hospital-acquired infections, belongs to the recently published WHO’s list of antibiotic-resistant pathogens that pose the greatest threat to human health. Indeed, K. pneumoniae is the enterobacterial species most concerned by both resistance to extended-spectrum cephalosporins, due to extended-spectrum β-lactamase (ESBL) production, and resistance to carbapenems, i.e. the β-lactams with the broadest activity. Carbapenem resistance is related not only to carbapenemase production, but also the production of ESBL or AmpC and the loss of general porins. Here, we characterized the mechanisms that deprived a urinary ESBL-producing, porin-deficient K. pneumoniae isolate, isolated 13 days after the end of a 40-day course of imipenem treatment, of its carbapenem resistance. These mechanisms were observed in two in-vivo derivatives of this isolate and consisted of mutations in genes encoding molecules that participate in the downregulation of the synthesis of PhoE, a porin specialized in phosphate transport. We obtained three new derivatives from one of the two original derivatives, following in-vitro antibiotic pressure, in which the carbapenem resistance was restored because of mutations in genes encoding molecules that participate in the upregulation of PhoE synthesis. Thus, we uncovered novel mechanisms of carbapenem resistance/susceptibility switching in K. pneumoniae.
Highlights
Klebsiella pneumoniae is a Gram-negative pathogen responsible for infections that are mainly hospital-acquired[1, 2]
The three isolates, called strains BJ-STC-a, BJ-STC-b, and BJ-STC-c, were tested by the agar-diffusion method and interpreted following the recommendations of the French Antibiogram Committee applicable in 2009. They were found to be resistant to extended-spectrum cephalosporins due to ESBL production, demonstrated by the double-disk synergy test[15], and gentamicin, amikacin, chloramphenicol, cotrimoxazole, and fluoroquinolones (Table 1). They differed from each other by susceptibility to four antibiotics (Table 1): strain BJ-STC-a was resistant to cefoxitin and ertapenem, had intermediate susceptibility to imipenem, and was susceptible to tigecycline, whereas strain BJ-STC-b was susceptible to the four antibiotics, and strain BJ-STC-c was susceptible to imipenem and resistant to cefoxitin, ertapenem, and tigecycline
The first urinary K. pneumoniae strain (BJ-STC-a) studied which was resistant to carbapenems, resembled those described in various UK hospitals in 2009 in terms of ESBL type produced (CTX-M-15) and genetic events leading to the loss of the general porins OmpK35 and Ompk[36] (IS1 or nucleotide insertion)[37]
Summary
Klebsiella pneumoniae is a Gram-negative pathogen responsible for infections that are mainly hospital-acquired[1, 2]. Two distinct mechanisms that cause resistance to carbapenems have been identified: acquisition of specific enzymes that hydrolyze carbapenems, called carbapenemases, such as KPC, OXA-48, and NDM5, and the combination of ESBL and/or AmpC production and alterations of porin synthesis[6, 7]. We showed that (i) the three isolates were isogenic strains, each possessing the mechanisms responsible for carbapenem resistance displayed by the first isolate and (ii) the second and third isolates displayed mutations in the pstSCAB-phoU genes that control the Pho regulon We demonstrated that these mutations were involved in the upregulation of the synthesis of the porin PhoE and the complete and partial susceptibility to carbapenems displayed by the second and third isolates, respectively. The authors did not identify the genetic cascades and molecular mechanisms involved in the carbapenem resistance/susceptibility switches
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