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Spectroscopic analysis and docking simulation on the recognition and binding of TEM-1 ?-lactamase with ?-lactam antibiotics.

ABSTRACT: The interaction between TEM-1 ?-lactamase and antibiotics is very important in the hydrolysis of antibiotics. In the present study, the recognition and binding of TEM-1 ?-lactamase with three ?-lactam antibiotics, including penicillin G, cefalexin and cefoxitin, was investigated by fluorescence and ultraviolet-visible absorption spectra in combination with molecular docking in the temperature range of 278-288 K and under simulated physiological conditions. The results demonstrated that the fluorescence emissions of TEM-1 ?-lactamase were extinguished by static quenching and the energy of TEM-1 ?-lactamase was transferred in a non-radioactive manner. The binding of TEM-1 ?-lactamase with the three antibiotics was a spontaneously exothermic process, with binding constants of 1.41×107, 7.81×106 and 5.43×104 at 278 K. Furthermore, binding was driven by enthalpy change and the binding forces between them were mainly hydrogen bonding and Van der Waals forces. A TEM-1 ?-lactamase only bound with one antibiotic at a time and the binding capacity between them was closely associated with the functional groups and flexibility in the antibiotics. In addition, a conformational change occurred in the TEM-1 ?-lactamases when they bound with the three antibiotics and TEM-1 ?-lactamase-antibiotic complexes were formed. The present study provided an insight into the recognition and binding of TEM-1 ?-lactamase with ?-lactam antibiotics, which may be helpful for designing a novel substrate for TEM-1 ?-lactamase and developing novel antibiotics that are resistant to the enzyme.

SUBMITTER: Yang J

PROVIDER: S-EPMC5585764 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Spectroscopic analysis and docking simulation on the recognition and binding of TEM-1 β-lactamase with β-lactam antibiotics.

Yang Jianting J Li Qian Q Bian Liujiao L

Experimental and therapeutic medicine 20170731 4

The interaction between TEM-1 β-lactamase and antibiotics is very important in the hydrolysis of antibiotics. In the present study, the recognition and binding of TEM-1 β-lactamase with three β-lactam antibiotics, including penicillin G, cefalexin and cefoxitin, was investigated by fluorescence and ultraviolet-visible absorption spectra in combination with molecular docking in the temperature range of 278-288 K and under simulated physiological conditions. The results demonstrated that the fluor ...[more]

PMID: 28912880

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Project description:Metallo-β-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-β-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available β-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64 mg/liter to 0.03 mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki ), which was 0.044 μM, and its inactivation constant (Kinact), which was 0.0406 min-1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization's priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Combination therapies involving a β-lactam antibiotic and a β-lactamase inhibitor remain a major treatment option for infections caused by β-lactamase-producing organisms. Currently, no MBL inhibitor-β-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

Dataset Information

Spectroscopic analysis and docking simulation on the recognition and binding of TEM-1 ?-lactamase with ?-lactam antibiotics.

Publications

Spectroscopic analysis and docking simulation on the recognition and binding of TEM-1 β-lactamase with β-lactam antibiotics.

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