In Silico Design and Molecular Docking Studies of Carbapenem Analogues Targeting Acinetobacter baumannii PBP1A Receptor
Keywords:Acinetobacter baumannii, Penicillin-Binding Proteins, Binding affinity, Drug-likeness properties.
Carbapenems are considered as the most effective antibiotic against Acinetobacter baumannii infections, as the pathogen has a resistance to the most of the other beta-lactam antibiotics; however, recent studies proved that this pathogen has developed
resistance to carbapenems, as well. Therefore, development of novel therapeutics targeting A. baumannii resistant strains is an urgent global requirement. One of the causes responsible for this bacterial resistance against beta-lactam antibiotics is the decreased strength of interactions between A. baumannii Penicillin-Binding Proteins 1A (PBP1A) and carbapenems. Therefore, the aim of this study is to design a novel analogue of imipenem with significantly higher binding affinity and improved drug-likeness properties to overcome resistance of the pathogen and optimize bioavailability, respectively. De novo drug design was performed using virtual screening to predict the ligand(s) with the highest binding affinity. The two-dimensional and three-dimensional structure of the designed molecules were sketched using Chemdraw professional and MarvinSketch, respectively. After separating the targeted protein from A. baumannii PBP1A-imipenem complex structure (3UDX) and retaining a monomer (chain A) from a dimer of the protein structure using Text Editor (ConTEXT v0.98.6), docking was achieved using virtual screening AutoDock Vina program. Finally, drug-likeness properties were assessed. The results could find the selected compounds with significantly higher binding affinity and improved physicochemical properties compared with imipenem.
- Shlaes DM, Bradford PA. Antibiotics-From There to Where? How the antibiotic miracle is threatened by resistance and a broken market and what we can do about it. Pathog Immun. 2018;3(1):19-43.
- Martyn G. Staphylococci in The Newborn: Their Coagulase Production and Resistance to Penicillin and Streptomycin. The British Medical Journal. 1949;1(4607):710-2.
- Tommasi R, Brown DG, Walkup GK, Manchester JI, Miller AA. ESKAPEing the labyrinth of antibacterial discovery. Nature reviews Drug discovery. 2015;14(8):529-42.
- Howard A, O'Donoghue M, Feeney A, Sleator RD. Acinetobacter baumannii: an emerging opportunistic pathogen. Virulence. 2012;3(3):243-50.
- Tiwari V, Kapil A, Moganty RR. Carbapenem-hydrolyzing oxacillinase in high resistant strains of Acinetobacter baumannii isolated from India. Microb Pathog. 2012;53(2):81-6.
- Wong D, Nielsen TB, Bonomo RA, Pantapalangkoor P, Luna B, Spellberg B. Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges. Clin Microbiol Rev. 2017;30(1):409-47.
- Morris FC, Dexter C, Kostoulias X, Uddin MI, Peleg AY. The Mechanisms of Disease Caused by Acinetobacter baumannii. Front Microbiol. 2019; 10:1601.
- Maragakis LL, Perl TM. Acinetobacter baumannii: epidemio-logy, antimicrobial resistance, and treatment options. Clin Infect Dis. 2008;46(8):1254-63.
- Freire MP, de Oliveira Garcia D, Garcia CP, Campagnari Bueno MF, Camargo CH, Kono Magri ASG, et al. Bloodstream infection caused by extensively drug-resistant Acinetobacter baumannii in cancer patients: high mortality associated with delayed treatment rather than with the degree of neutropenia. Clin Microbiol Infect. 2016;22(4):352-8.
- Roca I, Espinal P, Vila-Farres X, Vila J. The Acinetobacter baumannii Oxymoron: Commensal Hospital Dweller Turned Pan-Drug-Resistant Menace. Front Microbiol. 2012; 3:148.
- Tiwari V, Nagpal I, Subbarao N, Moganty RR. In-silico modeling of a novel OXA-51 from beta-lactam-resistant Acinetobacter baumannii and its interaction with various antibiotics. J Mol Model. 2012;18(7):3351-61.
- Yang HY, Lee HJ, Suh JT, Lee KM. Outbreaks of imipenem resistant Acinetobacter baumannii producing OXA-23 beta-lactamase in a tertiary care hospital in Korea. Yonsei Med J. 2009;50(6):764-70.
- Feizabadi M, Fathollahzadeh B, Taherikalani M, Rasoolinejad M, Sadeghifard N, Aligholi M, et al. Antimicrobial susceptibility patterns and distribution of blaOXA genes among Acinetobacter spp. Isolated from patients at Tehran hospitals. Jpn J Infect Dis. 2008;61(4):274-8.
- Hu WS, Yao SM, Fung CP, Hsieh YP, Liu CP, Lin JF. An OXA-66/OXA-51-like carbapenemase and possibly an efflux pump is associated with resistance to imipenem in Acineto-bacter baumannii. Antimicrob Agents Chemother. 2007;51(11):3844-52.
- Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007;51(10):3471-84.
- Evans BA, hamouda A, Amyes SGB. The Rise of Carbapenem-Resistant Acinetobacter baumannii. Current Pharmaceutical Design. 2013;19(00):16.
- Karam G, Chastre J, Wilcox MH, Vincent JL. Antibiotic strategies in the era of multidrug resistance. Crit Care. 2016;20(1):136.
- Antimicrobial resistance survellance in Europe. European Centre for Disease Prevention and Control. 2014.
- Hartman BJ, Tomasz A. Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. Journal of bacteriology. 1984;158(2):513-6.
- Gehrlein M, Leying H, Cullmann W, Wendt S, O’pferkuch W. Imipenem Resistance in Acinetobacter baumanii Is Due to Altered Penicillin-Binding Proteins. Chemotherapy. 1991; 37:405-12.
- Acosta J, Merino M, Viedma E, Poza M, Sanz F, Otero JR, et al. Multidrug-ResistantAcinetobacter baumanniiHarboring OXA-24 Carbapenemase, Spain. Emerging Infectious Diseases. 2011;17(6):1064-7.
- Brown S, Amyes S. OXA (beta)-lactamases in Acinetobacter: the story so far. J Antimicrob Chemother. 2006;57(1):1-3.
- Vashist J, Tiwari V, Rajeswari MR. Analysis of penicillin-binding proteins (PBPs) in carbapenem resistant Acinetobacter baumannii. The Indian Journal of Medical Research. 2011;133(3):332-8.
- Vashist J, Rajeswari MR. Structural investigations on novel porin, OmpAb from Acinetobacter baumannii. J Biomol Struct Dyn. 2006;24(3):243-53.
- Hakimelahi GH, Moosavi-Movahedi AA, Tsay S-C, Tsai FY, Wright JD, Dudev T, et al. Design, Synthesis, and SAR of Novel Carbapenem Antibiotics with High Stability to Xanthomonas maltophilia Oxyiminocephalosporinase Type II. J Med Chem. 2000; 43:3632-40.
- Isler B, Doi Y, Bonomo RA, Paterson DL. New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections. Antimicrobial Agents and Chemotherapy. 2019;63(1):1-17.
- Shaikh S, Fatima J, Shakil S, Rizvi SM, Kamal MA. Antibiotic resistance and extended spectrum beta-lactamases: Types, epidemiology and treatment. Saudi J Biol Sci. 2015;22(1):90-101.
- Rodloff AC, Goldstein EJ, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother. 2006;58(5):916-29.
- Livermore DM. Doripenem: antimicrobial profile and clinical potential. Diagn Microbiol Infect Dis. 2009;63(4):455-8.
- Shahid M, Sobia F, Singh A, Malik A, Khan H, Jonas D, et al. Beta-lactams and beta-lactamase-inhibitors in current-or potential-clinical practice: a comprehensive update. Critical reviews in microbiology. 2009;35(2):81-108.
- Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, et al. Comparative review of the carbapenems. Drugs. 2007;67(7):1027-52.
- El-Gamal MI, Oh CH. Current Status of Carbapenem Antibiotics. Current Topics in Medicinal Chemistry. 2010; 10:1882-97.
- Kapetanovic IM. Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach. Chemico-biological interactions. 2008;171(2):165-76.
- Parenti MD, Rastelli G. Advances and applications of binding affinity prediction methods in drug discovery. Biotechnology advances. 2012;30(1):244-50.
- Lengauer T, Rarey M. Computational methods for biomolecular docking. Current Opinion in Structural Biology. 1996; 6:402-6.
- Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nature reviews Drug discovery. 2004;3(11):935.
- Warren GL, Andrews CW, Capelli A-M, Clarke B, LaLonde J, Lambert MH, et al. A critical assessment of docking programs and scoring functions. Journal of medicinal chemistry. 2006;49(20):5912-31.
- ChemAxon M. www.chemaxon.com/products/marvin. Budapest: Jan; 2016.
- Berman H, Henrick K, Nakamura H. Announcing the worldwide Protein Data Bank. Nature Structural & Molecular Biology. 2003;10(12):980.
- Frances B, Thomas K, Graheme W, Edgar M, Michael B, John R, et al. The protein data bank: A computer-based archival file for macromolecular structures. Archives of Biochemistry and Biophysics. 1978;185(2):584-91.
- Han S, Caspers N, Zaniewski RP, Lacey BM, Tomaras AP, Feng X, et al. Distinctive attributes of beta-lactam target proteins in Acinetobacter baumannii relevant to development of new antibiotics. Journal of the American Chemical Society. 2011;133(50):20536-45.
- Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews. 1997;23(1-3):3-25.
- Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2012; 64:4-17.
- Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-61.
- Dallakyan S, Olson AJ. Small-Molecule Library Screening by Docking with PyRx. Chemical Biology. 1263: Springer; 2015. p. 243-50.
- Ashraf Z, Bais A, Manir MM, Niazi U. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies. PloS one. 2015;10(8): e0135293.
- Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: a review. Biophys Rev. 2017;9(2):91-102.
- Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF chimera - A visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605-12.
- Laskowski RA, Swindells MB. LigPlot+: multiple ligand–protein interaction diagrams for drug discovery. ACS Publications; 2011.
- Boucher HW, Talbot GH, Benjamin DK, Jr., Bradley J, Guidos RJ, Jones RN, et al. 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(12):1685-94.
- Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother. 2009;64 Suppl 1: i29-36.
- Codjoe F, Donkor E. Carbapenem Resistance: A Review. Medical Sciences. 2017;6(1).
- Kaneria M, Parmar J, Rakholiya K. Molecular docking and drug design of phytoconstituents from Couroupita guianensis – An in-silico perspective. Journal of Pharmacognosy and Phytochemistry. 2019;8(6):53-60.
- Machatha SG, Yalkowsky SH. Comparison of the octanol/water partition coefficients calculated by ClogP, ACDlogP and KowWin to experimentally determined values. Int J Pharm. 2005;294(1-2):185-92.
- Hansch C, Björkroth J, Leo A. Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. Journal of Pharmaceutical Sciences. 1987;76(9):663-87.
- Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chemical biology & drug design. 2013;81(1):136-47.
- Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature reviews Drug discovery. 2007;6(11):881-90.