An Overview Of New Effective Metallo-ß-lactamase Inhibitors Against ß-lactamase Resistant Bacterias

5th International Symposium On Multidisciplinary Studies, Ankara, Turkey, 16 - 17 November 2018, pp.659, (Full Text)

Publication Type: Conference Paper / Full Text
City: Ankara
Country: Turkey
Page Numbers: pp.659
Istanbul University Affiliated: Yes

Abstract

ß-lactam antibiotics are among the most often used antibacterial agents worldwide and the increasing resistance to these drugs constitutes a serious public health concern. Beta-lactamases have the key role in the development of resistance to ß-lactam antibiotics. They inactivate the ß-lactam antibiotics by breaking the ß-lactam ring of their chemical structure. ß-lactamases are composed of 4 classes A, B, C and D. Class A, C and D are members of serine protease type enzymes. The Class-B is different from the other types and can be spread by mobile genetic elements. The group B is called as zinc-based metallo-ß-lactamases (MBLs) which can hydrolyse almost all clinically-available ß-lactam antibiotics. ß-lactam antibiotics have a broad spectrum of antibacterial activity. This spectrum includes some serious and the most common Gram-positive and Gram-negative bacteria too. ß-lactam antibiotics show their activity by inhibiting the enzymes called as transpeptidases (Also named as penicillin binding proteins or PBPs) which have the main role for the synthesis of the peptidoglycan layer of the bacterial cell wall. As the defence mechanism against ß-lactam antibiotics, bacteria have developed a few type of biochemical mechanisms to deactivate the effect of ß-lactam antibiotics. ß-lactamase enzymes are an important and major group of defence mechanisms of bacteria and they decrease the activity of ß-lactam antibiotics thus causing antibiotic-resistance. ß-lactamases, a very old (and formerly rare) class of enzymes, have evolved rapidly after the introduction of ß-lactam antibiotics into clinical use. More than 470 known different ß-lactamases are present. There are effective ß-lactamase inhibitors against class A, C and D (such as sulbactam, tazobactam, clavulanic acid), whereas only a few number of effective inhibitors against class B metallo-ßlactamases present. In order to cope with developing antibiotic resistance, there is an urgent need to discover effective inhibitory agents against class B metallo-ß-lactamases. As a first step of our study all metallo-ß-lactamase inhibitors up to now were examined. We investigated, with which level and in which step the molecules show biological activity against metallo-ßlactamases. We evaluated the therapeutic activity in detail. Finally, we designed potentially active and original molecules as metallo-ß-lactamase inhibitors by taking advantage of computer-aided drug design. In such an effort, we carried out in silico simulations using Schrödinger software to determined binding modes of the compounds with the metallo-ßlactamase target and calculated potential drug likeness and other properties that are related to absorption, distribution, metabolism, excretion, toxicity (ADMET) of those compounds. The overall results obtained from molecular modelling studies and the pharmacological responses of the molecules synthesized as metallo-ß-lactamase inhibitors can provide insight for the synthesis of more efficient metallo-ß-lactamase inhibitors which might also have higher selectivity and activity. In addition, the present study also provides scientists a wide data resource related to the ß-lactamase inhibitors and antibiotic resistance, thus helping them perform a more organized and fertile drug discovery operation.