Sandbox Reserved 1241

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].

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.