RESUMEN
Acinetobacter baumannii infections are associated with a high mortality rate. Sulbactam, a beta-lactamase inhibitor, is commonly used to treat A. baumannii infections, but its underlying mechanisms are unclear. Two-component regulatory systems (TCSs) are important for bacterial adaptability and response ability. In this study, we focused on two TCSs, namely AdeSR and BaeSR, and identified a protein highly similar to the dimerization and histidine phosphotransfer (DHp) and catalytic ATP-binding (CA) domains of the TCSs by using Swiss-Model. Sulbactam and ß-lactamase inhibitors, which are structurally similar to sulbactam, were docked with the selected sequence 4JAS using the simulation tools SwissDock and ArgusLab. Analysis with both these analytical tools showed that sulbactam can react on the active sites of 4JAS at a relatively steady level (ΔG -7 to -10 kcal/mol). Sulbactam likely interacts with the active sites of BaeSR and AdeSR, and owing to its smaller size and ability to form ionic bonds with Mg2+, it may potentially compete with ATP/ADP in BaeSR and AdeSR and consequently interfere with A. baumannii multiplication. This is the first study to investigate the association between sulbactam and TCSs in A. baumannii using molecular docking and simulation analyses.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Sulbactam/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/química , Acinetobacter baumannii/metabolismo , Proteínas Bacterianas/química , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento MolecularRESUMEN
Acinetobacter baumannii has been associated with several severe hospital-acquired infections such as ventilator-associated pneumonia and meningitis. Sulbactam, a ß-lactamase inhibitor, is usually combined with ß-lactam antibiotics to treat infections. It has been found that sulbactam alone may be used to treat infections caused by A. baumannii, although the mechanism of the bactericidal effect remains unknown. In this study, proteomics was used to analyse protein intensity changes and to identify the proteins of A. baumannii following sulbactam treatment. In total, 54 proteins were found to exhibit significant changes in intensity. Proteins with reduced intensity included ATP-binding cassette (ABC) transporters as well as 30S and 50S ribosomal subunit proteins. These proteins are essential for nutrient import and protein synthesis and are vital for bacterial survival. The amplified proteins included glutamine synthetase, malic enzyme, RNA polymerase subunit α, and the molecular chaperones DnaK and GroEL, which function in metabolism, DNA and protein synthesis, and repair machinery. These amplified proteins were increased to rescue bacteria, however they could not overcome the effects of the reduced proteins and the bacteria were killed. This is the first report that the reduction of ABC transporters and 30S and 50S ribosomal subunit proteins plays an important role in the bactericidal effect of sulbactam against A. baumannii.