Citation: Drioiche, A.; Baammi, S.; Zibouh, K.; Al Kamaly, O.; Alnakhli, A.M.; Remok, F.; Saidi, S.; Amaiach, R.; El Makhoukhi, F.; Elomri, A.; et al. A Study of the Synergistic Effects of Essential Oils from Origanum compactum and Origanum elongatum with Commercial Antibiotics against Highly Prioritized Multidrug-Resistant Bacteria for the World Health Organization. Metabolites 2024, 14, 210. https:// doi.org/10.3390/metabo14040210 Academic Editors: Luke E. K. Achenie and Andres Fernando Gonzalez Barrios Received: 14 March 2024 Revised: 30 March 2024 Accepted: 2 April 2024 Published: 7 April 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). metabolites H OH OH Article A Study of the Synergistic Effects of Essential Oils from Origanum compactum and Origanum elongatum with Commercial Antibiotics against Highly Prioritized Multidrug-Resistant Bacteria for the World Health Organization Aziz Drioiche 1,2, * , Soukayna Baammi 3 , Khalid Zibouh 1 , Omkulthom Al Kamaly 4 , Anwar M. Alnakhli 4 , Firdaous Remok 1 , Soukaina Saidi 1 , Rachid Amaiach 5 , Fadoua El Makhoukhi 1 , Abdelhakim Elomri 6 and Touriya Zair 1, * 1 Research Team of Chemistry of Bioactive Molecules and the Environment, Laboratory of Innovative Materials and Biotechnology of Natural Resources, Faculty of Sciences, Moulay Ismail University, B.P. 11201, Zitoune, Meknes 50070, Morocco; k.zibouh@edu.umi.ac.ma (K.Z.); f.remok@edu.umi.ac.ma (F.R.); soukaina.saidi@usms.ma (S.S.); elmakhoukhi@cnrst.ma (F.E.M.) 2 Medical Microbiology Laboratory, Mohamed V. Hospital, Meknes 50000, Morocco 3 Bioinformatics Laboratory, College of Computing, Mohammed VI Polytechnic University, Ben Guerir 43150, Morocco; soukayna.baammi@um6p.ma 4 Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; omalkmali@pnu.edu.sa (O.A.K.); amalnklee@pnu.edu.sa (A.M.A.) 5 Laboratory of Materials, Processes, Catalysis and Environment, School of Technology, University Sidi Mohamed Ben Abdellah, Fez 30000, Morocco; rachid.amaiach@usmba.ac.ma 6 UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), Normandie University, 76000 Rouen, France; hakim.elomri@univ-rouen.fr * Correspondence: a.drioiche@edu.umi.ac.ma (A.D.); t.zair@umi.ac.ma (T.Z.); Tel.: +212-600394841 (A.D.) Abstract: The irrational use of antibiotics has favored the emergence of resistant bacteria, posing a serious threat to global health. To counteract antibiotic resistance, this research seeks to identify novel antimicrobials derived from essential oils that operate through several mechanisms. It aims to evaluate the quality and composition of essential oils from Origanum compactum and Origanum elongatum; test their antimicrobial activity against various strains; explore their synergies with commercial antibiotics; predict the efficacy, toxicity, and stability of compounds; and understand their molecular interactions through docking and dynamic simulations. The essential oils were extracted via hydrodistillation from the flowering tops of oregano in the Middle Atlas Mountains in Morocco. Gas chromatography combined with mass spectrometry (GC-MS) was used to examine their composition. Nine common antibiotics were chosen and tested alone or in combination with essential oils to discover synergistic effects against clinically important and resistant bacterial strains. A comprehensive in silico study was conducted, involving molecular docking and molecular dynamics simulations (MD). O. elongatum oil includes borneol (8.58%), p-cymene (42.56%), thymol (28.43%), and carvacrol (30.89%), whereas O. compactum oil is mostly composed of γ-terpinene (22.89%), p-cymene (15.84%), thymol (10.21%), and (E)-caryophyllene (3.63%). With O. compactum proving to be the most potent, these essential oils showed antibacterial action against both Gram-positive and Gram-negative bacteria. Certain antibiotics, including ciprofloxacin, ceftriaxone, amoxicillin, and ampicillin, have been shown to elicit synergistic effects. To fight resistant bacteria, the essential oils of O. compactum and O. elongatum, particularly those high in thymol and (E)-caryophyllene, seem promising when combined with antibiotics. These synergistic effects could result from their ability to target the same bacterial proteins or facilitate access to target sites, as suggested by molecular docking simulations. Molecular dynamics simulations validated the stability of the examined protein–ligand complexes, emphasizing the propensity of substances like thymol and (E)-caryophyllene for particular target proteins, opening the door to potentially effective new therapeutic approaches against pathogens resistant to multiple drugs. Metabolites 2024, 14, 210. https://doi.org/10.3390/metabo14040210 https://www.mdpi.com/journal/metabolites