br MCADD review br Funding None

MCADD review
Funding None.
Introduction Bacteroides species are obligate anaerobes, Gram-negative, and non-spore-forming bacteria and 21 species of this genus are found particularly in the oral cavity and gastrointestinal tract in vertebrates [1,2]. B. fragilis is the most common Zafirlukast pathogen that has been isolated clinically although it composes only 0.5% of the human colonic flora [3]. Enterotoxigenic B. fragilis (ETBF) is the only strain that is related to various diseases including colon cancer [1]. Despite the most effective antibiotics used against B. fragilis, among which are penicillins, cephalosporins, carbapenems, clindamycin and metronidazole, it has developed resistance to antibiotics [[4], [5], [6], [7]]. The World Health Organization has pointed out an increase in antimicrobial resistance and the need of development of new classes of antibiotics in the short term on Global Action Plan on Antimicrobial Resistance [8]. Because of potential drug resistant of bacteria, success rates are low at research of antimicrobial drugs and more efficient solutions are needed [9]. Structure based drug design is a method used to develop new drugs and refers specifically to finding the active site of target molecules such as enzymes, proteins and nucleic acids [10]. Lactate dehydrogenase (LDH) is an enzyme that provides sustainability of glycolysis in anaerobic respiration by catalysing reversible conversion of pyruvate to lactate and also by transferring internal NAD+ cycles [11,12]. As the B. fragilis also use this pathway. B. fragilis d‑LDH has been chosen as a target enzyme for inhibition studies. To the best of our knowledge, this study is the first in the literature to target and demonstrate the inhibition of Bfd‑LDH. Coumarins are one of the most common phenolic secondary metabolites of various plants [12] and have broad biological activities such as anticancer, antimicrobial, anti-depressant, anti-inflammatory, anti-viral, anti-hypertensive, anti HIV1, anti-coagulant, and anti-fungal [[13], [14], [15]]. This study aims testing inhibitory capacity and structural relations of coumarin derivatives on d‑LDH, to determine the potential lead of these compounds as an important step of structure based drug design.
Experimental section
Results and discussion
Conclusion Following the association of B. fragilis with colon cancer [1], the reports on antibiotic resistance revealed the need for development of new drugs. This study has been the first inhibition study applied on Bfd‑LDH. The high inhibition results are encouraging for future in vivo studies and because of the fact that there is not a human homolog of the enzyme, despite Bfd‑LDH transfers internal NAD+ cycles in glycolysis, human d‑LDH uses cytochrome as an acceptor [25,26]. A series of novel coumarin derivatives were evaluated for Bfd‑LDH inhibitory activity. Most of the compounds showed high Bfd‑LDH inhibitory activity. In the present study, inhibitory effect of a series of 3- and 4-arylcoumarin derivatives on Bfd‑LDH has been investigated, and three arylcoumarin derivatives (6a, 5l and 6b) have been identified as the most potent inhibitors with the IC50 values of 0,47 μM, 0,57 μM, and 0,05 μM, respectively. Enzyme inhibition mechanism and kinetic parameters of the enzymatic reaction were also analysed in detail for these coumarin derivatives and it was determined that the inhibition of Bfd‑LDH by these compounds is provided via a non-competitive inhibition mechanism (Ki values for 6a, 6b and 5l were 0.4532, 0.5183 and 0. 3603 μM, respectively).Docking studies clarified that the coumarin derivatives interact with active residues of the enzyme. Further work will focus on cell culture studies of three coumarin derivatives that have been found to be the most effective inhibitors on Bfd‑LDH as drug candidates. We suggest that these coumarin derivatives discovered here would provide novel lead compounds in drug design efforts to combat B. fragilis infections.