Monday, January 05, 2015

A snippet on NDM: A special β-lactamase


In the era of antibiotics, the factor of drug resistance is a matter of discussion. The problem has escalated from the resistance to a couple of antibiotics to Pan drug resistance, which means there is nothing in the approved antibiotic pipeline that can be used. In desperation, attempts have been made to use research drugs. Literature is full of examples. A point has come where the types of Antibiotic resistance has become a database in its own right. In general, gram negative bacteria tends to have resistance to a wider range of resistance than the gram positive types.

Fig 1: Structure of NDM-1.
Of these, one of the most recent discovery is a resistance type- NDM (New Delhi Metallo Beta Lactamase). Its is a molecular type B- β lactamase. Unlike other molecular types (A, C and D), this enzyme has zinc ions at its active site, and it can hydrolyze most of the β-lactam drugs. Moreover, it has been seen that the organism carrying the NDM phenotype, is also resistant to multiple other drugs. Claims have been that NDM positive isolates have up to 14 other antibiotic resistance determinants. This makes them a formidable opponent to antibiotic treatment.

One of the most relied drug of use against drug resistant bugs was the carbapenem class. Though carbapenemase phenotypes were known before the discovery of NDM, it was the most versatile of all. The first case was demonstrated in 2009, in a Swedish patient. It has been suggested that NDM carrying plasmid was circulating in New Delhi as early as 2006. The original identified sequence is called as NDM-1. NDM-1 has been demonstrated widely in multiple geographical regions and multiple species. It appears from the literature that a large chunk of cases are represented by Klebsiella species, E coli and Acinetobacter species, predominantly from Asian countries.

Antibiotic resistance is a phenomenon tagged with antibiotic use. Though it has been argued that the chunk of first described cases were associated with India, it is unfair to claim that the strains have originated in India. Rightly so, the nomenclature stirred a huge debate and Lancet editor apologized for publishing by that name. It has been proposed that NDM should be renamed to PCM (plasmid-encoding carbapenem-resistant metallo-β-lactamase). However, the term NDM is extensively engraved in the literature.
Table 1: NDM variants.

The original sequence of NDM, has spread across the globe and variants have been emerging. To the best that I know of to date, there are 8 varieties of NDM (named from NDM-1 through 8). I have provided a summary of the features in table 1. As you can see from the table, the variation in NDM is just 1 or 2 point mutations. Since mutations are common (as you can see from ESBL subtypes; there are a zillion differences), does designation as a variant hold. Studies have shown that each variant has a different profile of resistance with varying MIC. Also the structural stability kinetics of the enzyme themselves are significantly different between each, and hence designation into separate entities qualify.
Liang Z, Li L, Wang Y, Chen L, Kong X, Hong Y, Lan L, Zheng M, Guang-Yang C, Liu H, Shen X, Luo C, Li KK, Chen K, & Jiang H (2011). Molecular basis of NDM-1, a new antibiotic resistance determinant. PloS one, 6 (8) PMID:2188728

Berrazeg M, Diene S, Medjahed L, Parola P, Drissi M, Raoult D, & Rolain J (2014). New Delhi Metallo-beta-lactamase around the world: an eReview using Google Maps. Euro surveillance 19 (20) PMID:24871756

Singh AR (2011). Science, Names Giving and Names Calling: Change NDM-1 to PCM. Mens sana monographs, 9 (1), 294-319 PMID:21694981

Makena A, Brem J, Pfeffer I, Geffen RE, Wilkins SE, Tarhonskaya H, Flashman E, Phee LM, Wareham DW, & Schofield CJ (2014). Biochemical characterization of New Delhi metallo-β-lactamase variants reveals differences in protein stability. The Journal of antimicrobial chemotherapy PMID: 25324420

Tatsuya Tadaa, Tohru Miyoshi-Akiyamaa, Rajan K. Dahalc, Manoj K. Sahc, Hiroshi Oharab, Teruo Kirikaea and Bharat M. Pokhrelc (2013). NDM-8 Metallo-β-Lactamase in a Multidrug-Resistant Escherichia coli Strain Isolated in Nepal Antimicrob. Agents Chemother. doi : 10.1128/AAC.02553-12

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