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Antibiotic resistance is considered a major health concern globally. It is a fact that the clinical need for new antibiotics was not achieved until now. One of the most commonly prescribed classes of antibiotics is β-Lactam antibiotics. However, most bacteria have developed resistance against β-Lactams by producing enzymes β-Lactamase or penicillinase. The discovery of new β-Lactamase inhibitors as new antibiotics or antibiotic adjuvants is essential to avoid future catastrophic pandemics. In this study, five dihydroisocoumarin: 6-methoxy mellein (1); 5,6-dihydroxymellein (2); 6-hydroxymellein (3); 4-chloro-6-hydroxymellein (4) and 4-chloro-5,6-di-hydroxymellein (5) were isolated from Wadi Lajab sediment-derived fungus <i>Penicillium chrysogenum</i>, located 15 km northwest of Jazan, KSA. The elucidation of the chemical structures of the isolated compounds was performed by analysis of their NMR, MS. Compounds <b>1</b>–<b>5</b> were tested for antibacterial activities against Gram-positive and Gram-negative bacteria. All of the compounds exhibited selective antibacterial activity against Gram-positive bacteria <i>Staphylococcus aureus</i> and <i>Bacillus licheniformis</i> except compound <b>3</b>. The chloro-dihydroisocoumarin derivative, compound <b>4</b>, showed potential antimicrobial activities against all of the tested strains with the MIC value between 0.8–5.3 μg/mL followed by compound <b>5</b>, which exhibited a moderate inhibitory effect. Molecular docking data showed good affinity with the isolated compounds to β-Lactamase enzymes of bacteria; NDM-1, CTX-M, OXA-48. This work provides an effective strategy for compounds to inhibit bacterial growth or overcome bacterial resistance.