Each compound in our database includes its SMILES format, which is commonly used in in silico analyses

Each compound in our database includes its SMILES format, which is commonly used in in silico analyses. 4.2. be interactive, and the site will be improved in the future as researchers use the site and suggest improvements. It is hoped that will serve as the one-stop site for any important information on MBL inhibitors and will aid in the discovery of a clinically useful MBL inhibitor. strong class=”kwd-title” Keywords: antibiotic resistance, metallo–lactamase, website, inhibitor, 1. Introduction Antibiotic resistance is becoming an increasingly Bupropion important biomedical issue, turning what was once easily treated with inexpensive and easily-accessible antibiotics into untreatable infections [1]. According to the Centers for Disease Control and Prevention (CDC), 2.8 million infections occur from antibiotic-resistant bacteria in the U.S. each year, with about 35,000 deaths from these infections [2]. The World Health Organization (WHO) predicts that over 10 million deaths, as well as an economic loss of $10 trillion, will occur annually if effective intervention is not implemented [3]. Since the discovery of penicillin by Fleming in 1929, the -lactam class remains the largest class of antibiotics for the treatment of bacterial infections, making up 65% of the antibacterial arsenal [4]. Penicillins, cephalosporins, carbapenems, and monobactams are all members of the -lactam class [5]. The widespread use of this class of antibiotics has led to the emergence of different resistance mechanisms, including: (a) the production of altered penicillin binding proteins (PBP) with lower binding affinities for most -lactam antibiotics; and (b) the production of -lactamases, which is the most common resistance mechanism in Gram-negative bacteria [6]. In 2019, there are more than 2800 identified -lactamase genes [7]. They have been classified biochemically into two categories according to the mechanism by which they hydrolyze the -lactam bond [8]. The serine–lactamases (SBL) utilize an active site serine to hydrolyze the -lactam bond. The metallo–lactamases (MBL) utilize Zn(II)-containing active sites to hydrolyze the -lactam bond in these antibiotics [9]. Although the SBLs are more prevalent in the clinic over the past seventy years, there exist inhibitors, which can be given in combination with other -lactam containing antibiotics, to treat bacteria that produce some of the SBLs [10]. Examples of these FDA-approved inhibitors include clavulanic acid, sulbactam, avibactam, and tazobactam [10]. However, despite considerable efforts to develop such inhibitors [6], there are no clinically-approved inhibitors that are available for MBLs, making infections from bacteria that produce MBL a serious challenge. An ideal MBL inhibitor would have good inhibition properties, low toxicity, and is broad-spectrum [11]. Three major challenges have limited success in preparing a clinical inhibitor of the MBLs. Firstly, there are large structural variances exhibited by the MBLs, even those from the same molecular subclass [12]. There are Bupropion three subclasses of MBLs; B1, B2, and B3, and members are distinguished by amino acid sequence, molecular properties, identity of Zn(II)-coordinating ligands, and the number of active site metal ions present [9]. Across these subclasses, there is less than 20% amino acid sequence identities [13]. In the B1 subclass alone, there is only a modest 30% amino acid sequence similarities, with only a few highly-conserved residues present outside the Zn(II)-binding site [12]. This structural Bupropion diversity has resulted in MBL inhibitors that inhibit only one (or a few) MBL, but not others. For example, the dicarboxylic acid compound ME1071 was reported to be a good inhibitor of MBL IMiPenemase (IMP-1) and VIM-2 Verona Integron-borne MBL Bupropion (VIM-2) [14]. However, this compound is a poor inhibitor of subclass B1 MBL NDM-1 New Delhi MBL (NDM)-1) Rabbit Polyclonal to DGKB [15]. Another example is the bicyclic boronate VNRX-5133, which exhibits good inhibition against NDM and other subclass B1 enzymes [16]; however, this compound is not a good inhibitor of subclass B3 MBL L1 [16]. Secondly, it is imperative that any clinical MBL inhibitor be selective towards bacterial MBLs over human MBL-fold containing enzymes, some of which have important physiological roles [6]. The most common (and perhaps most obvious) way to inhibit an MBL is through the use of a.