Summary Klebsiella is a Gram-negative bacterium that belongs to the family Enterobacteriaceae. Klebsiella pneumoniae is the most medically important Klebsiella species and one of the major opportunistic pathogens associated with hospital outbreaks. K. pneumoniae can colonize asymptomatically the intestinal tract, skin, nose and throat of healthy individuals. However, K. pneumoniae could cause various infections in hospitalized patients, most commonly pneumonia, wound, soft tissue, and urinary tract infections. K. pneumoniae infections are particularly a problem among neonates, the elderly, and immunocompromised patients. In addition K. pneumoniae can cause significant number of serious community-acquired infections including pyogenic liver abscess, pneumonia, and meningitis. β–lactam is the largest and most important class of antibiotics that have different sub-classes including penicillins, cephalosporins, carbapenems and monobactam. β–lactam antibiotics are widely used in treatment of K. pneumonia infections. Bacterial resistance to β–lactam-antibiotics has increased dramatically with the production of β-lactamases. Carbapenems are among the last-line antibiotics that are used against resistant Gram-negative bacteria. The rapid dissemination of carbapenem-resistant Enterobacteriaceae (CRE) especially Carbapenem resistant-Klebsiella (CRK) represents a global public health threat. Carbapenem-resistance occurs mainly due to production of various types of carbapenemases. Based on the molecular structure and amino acid sequences (ambler classes), carbapenemases belong to three classes including: class A and D enzymes that depend on serine for β-lactams hydrolysis and class B metallo-betalactamase (MBLs) which use divalent zinc ions for substrate hydrolysis. In Enterobacteriaceae, the most prevalent class A-carbapenemases is the Klebsiella pneumoniae carbapenemase (KPC). The class B MBLs mainly include New Delhi MBL (NDM), Verona Integron-encoded MBL(VIM), and IMP-type carbapenemase. While the most frequently detected class D is the OXA-type β-lactamases [8]. Other carbapenem resistance mechanisms include loss of expression or mutation of porin-encoding genes and overexpression of genes encoding efflux pumps. Carbapenem resistance in Gram-negative pathogens is dramatically limiting treatment options, it is obvious that novel therapies are urgently needed. Recently, new carbapenemase inhibitors with activity against CRE have been approved for clinical use including avibactam, relebactam, and vaborbactam. The development of these inhibitors represents a step in the fight against antimicrobial resistance that needs to be followed by further steps. This study aims to evaluate the antibacterial activity and the carbapenemases inhibitory activity of the phytochemicals celasterol, thymol and cumarin in order to provide possible options to combat carbapenem-resistant K. pneumoniae. Clinical Klebsiella isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk diffusion method. Carbapenemase production was tested phenotypically and by PCR-based methods. Among the 85 clinical Klebsiella isolates identified in this study, 72 were multi-drug resistant (MDR) and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, blaNDM1 was detected in 35 isolates, blaVIM in 17 isolates, blaOXA in 18 isolates, while blaKPC was detected only in 6 isolates. Celastrol is a pentacyclic triterpenoid that belongs to a category of natural products named triterpene quinine methides. Celastrol was evaluated in this work in combination with meropenem. Celastrol showed a significant inhibitory effect against the carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol alone, and only a 2-fold decrease in meropenem-MIC was observed in the presence of thymol, while 4-64 fold decrease in meropenem-MIC was observed when meropenem was combined with both celastrol and thymol. Furthermore, sub-MIC of thymol increased CRK cell wall permeability. A molecular docking study for binding with carbapenemases revealed that celastrol is superior to thymol for KPC binding followed by VIM-carbapenemase. Coumarin occurs naturally as a sweet-smelling compound that belongs to a broad class of compounds of benzopyrones (1,2-benzopyrones or 2H-1-benzopyran-2-one). Sub-MIC (1000 μg/mL) of coumarin inhibited meropenem hydrolytic activities of extracted carbapenemases when co-incubated with the pooled periplasmic extract with mean inhibitory percentage of 57.33±7.59. coumarin have an inhibitory action on the expression of carbapenemases encoding genes. This finding was supported by qRT-PCR results. The inhibition zone around the meropenem disk was significantly increased in dose-dependent matter when the bacteria were cultured in the presence of coumarin from that of meropenem alone. The synergism was also clearly manifested when checkerboard MIC assay was performed as the fractional inhibitory concentration (FIC) index of the coumarin meropenem combination was lower than 0.5 indicating synergism. This study showed that celastrol, thymol, and coumarin could be used to render CRK sensitive to meropenem as suggested by its inhibitory activity on both the hydrolytic activity and the expression of carbapenamses making it possible solution to overcome carbapenems resistance.