Characterization of a New Metallo-β-Lactamase Gene, bla _NDM-1 , and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India

Abstract

A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type 14 complex. The isolate, Klebsiella pneumoniae 05-506, was shown to possess a metallo-␤-lactamase (MBL) but was negative for previously known MBL genes. Gene libraries and amplification of class 1 integrons revealed three resistanceconferring regions; the first contained bla CMY-4 flanked by ISEcP1 and blc. The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7. An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated bla NDM-1 , flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side. The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity. As well as possessing unique residues near the active site, NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs. NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all ␤-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2. In addition to K. pneumoniae 05-506, bla NDM-1 was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation. The broad resistance carried on these plasmids is a further worrying development for India, which already has high levels of antibiotic resistance.

The role of vaccines in fighting antimicrobial resistance (AMR)

“…A resistant strain was isolated in patients in Europe who had previously traveled to India for surgical procedures 10 , 11 (Figure 1) and NDM-1 subsequently spread to other Gram-negative species conferring resistance to all agents except colistin and tigecycline. MCR-1 plasmid-1 introduction into Escherichia coli isolates enabling resistance to the last line antibacterial agent colistin, now raises the concern that strains containing both MCR-1 and NDM-1 may emerge that may make routine outpatient urinary tract infections untreatable.…”

Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes

“…Indeed, environmental reservoirs have been identified for a number of recently-emerged and rapidly-disseminating resistance genes representing urgent clinical threats (e.g. plasmid-borne and chromosomally-acquired carbapenem 10 , colistin 11 , and quinolone 12 resistance genes). This motivates the need to better understand resistance mechanisms of environmental origin before they are widespread in the clinic and ultimately guide new drug discovery and therapeutic strategies that mitigate emerging mechanisms of resistance.…”

Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

“…9 MβLs are further divided into subclasses B1−B3, based on amino acid sequence homologies and Zn(II) content. 10 New Delhi metallo-β-lactmase-1 (NDM-1), a B1 subclass enzyme first discovered in 2008, 11 has become a global threat because it confers resistance to almost all β-lactam antibiotics and due to its rapid spread of the plasmid-encoded NDM-1 gene. 12,13 The inhibitors of serine-β-lactamases (classes A, C, and D), such as tazobactam and sulbactam, have been used in combination with penicillins to treat infections with resistant bacteria.…”