New Delhi metallo-β-lactamase (NDM-1) is a known enzyme that causes bacteria resistance against a large range of β-lactam antibiotic drugs. β-lactam antibiotics act by inhibiting the synthesis of cell wall layers and because the bacteria are unable to form cell walls they undergo lysis [1]. NDM-1, however, hydrolyzes the amide bond and inactivates the β-lactam antibiotics and allows the bacterial infections to thrive [2].
NDM-1 refers to a transmissible genetic element encoding multiple resistance genes. The gene from NDM-1 is capable of spreading from one strain of bacteria to a different strain through the use of horizontal gene transfer [3]. The initial strain, was isolated from a strain of Klebsiella pneumoniae that was obtained from a Swedish patient who acquired a urinary tract infection while traveling in New Delhi, India in 2008 [4]. Consequently, NDM-1has been found in organisms containing the genetic element throughout India, Pakistan, Bangladesh, the United Kingdom [5], Japan [6], and the United States.
Function
New Delhi metallo- β -lactamase 1 has the capability of making bacteria resistant to a variety of β-lactam antibiotics, including the mainstay antibiotics that can treat antibiotic-resistant bacterial infections. These mainstay antibiotics include the carbapenem family antibiotics which are extremely powerful drugs that can fight highly resistant bacteria [1]. Carbapenems work by inhibiting the synthesis of cell wall layers in bacteria. The gene, blaNDM-1, produces NDM-1 (a carbapenemase beta-lactamase) that can hydrolyze and inactivate the carbapenem antibiotics [7]. The resistance that blaNDM-1 confers, aids in the expansion of the bacteria that carries the gene throughout the human host.
Spread
NDM-1 was discovered to have originated in India [4]. The enzyme has been found in different water sources throughout India [8]. It is believed that spreading of NDM-1 can occur through bone marrow or renal transplantation, cerebral infarction, dialysis, chronic obstructive pulmonary disease (COPD), burns, cosmetic surgery, pregnancy, and road traffic incidents [9]. Since discovery, New Delhi metallo- β -lactamase 1 has spread to other countries by people who have spent some amount of time in India [8]. NDM-1 has confirmed cases in Australia, Japan, the United Kingdom, the United States, as well as a few other places [5].
NDM-1’s genetic code is able to spread from one bacteria strain to another through horizontal gene transfer [3]. This is a major concern because the new antibiotic-resistant infections could immerge from the NDM-1 enzyme and become untreatable. Currently, patients who have obtained the New Delhi metallo- β -lactamase 1 enzyme are treated on a case-by-case basis with different combinations of medications. The only way to fight the spread of NDM-1 is through quick identification, isolation, disinfection, and proper hygiene.
Structure
New Delhi metallo- β -lactamase 1 has been found to be part of the Metallo- β -lactamase (class B) family as well as the α /β structural class [10]. NDM-1 is composed of 158 amino acids[10] and works by catalyzing the substrate amide bond through hydrolytic cleavage [9].
New Delhi metallo- β -lactamase 1 contains two Zn+2 binding sites and other divalent cations that function as cofactors. The first Zn+2 binding site contains identical coordinating residues, His120-His122-His189, and the second Zn+2 binding site contains Asp124-Cys208-His250 residues [11]. The distance between these two binding sites is approximated to be 3.5 Å to 4.6 Å [11]. These two Zn+2 binding sites coordinate with the lactam oxygen and carboxyl oxygen atoms found on the NDM-1 structure [9]. This coordination contributes to the polarization of the lactam bond. In between the two Zn+2 binding sites, is a water molecule that during β-lactam hydrolysis acts as the nucleophile[9]. Research suggests that NDM-1 can use manganese or cadmium as a substitute for zinc and has the ability to bind substrates using different metals in the catalytic core [11].
NDM-1’s active site is made up of two mobile loops. The loops are crucial for recognition of substrate, binding, and catalysis. Loop 1 (also known as the flapping loop) is comprised of amino acids LDMPGFGAVA [9]. Within the middle of loop 1, there is a Phe70 benzene ring [9]. As for loop 2, Arg185 and Asn190 are important for substrate binding, catalysis, and inhibition through H-bond interactions [9]. Lys125 and Tyr229 play a role in stabilizing the conformation of the active site through the H-bond interaction [9]. Research showed that through the evolution of loop2, into a more positive charge caused the NDM-1 positive strain to become more potent and extensive in antibiotic resistance [9].
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