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Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant global health threat, necessitating the development of new therapeutic agents. Pleuromutilin derivatives offer a promising solution due to their potent antibacterial activity, particularly against Gram-positive bacteria such as MRSA. In this study, we synthesized a series of pleuromutilin derivatives with phenol linker containing C14 side chains and evaluated in vitro and in vivo antibacterial activities. Several compounds showed potent activity against MRSA and Staphylococcus aureus with minimal inhibitory concentrations (MICs) as low as 0.03125 μg/mL. In particular, compounds a4 and b4 showed rapid bactericidal activity, significantly reducing MRSA loads in time-kill kinetics and exhibiting slower resistance development compared to tiamulin. In vivo, compound a4 showed superior efficacy in reducing MRSA-induced lung damage in a mouse model at a lower effective dose (ED50 = 6.48 mg/kg) compared to tiamulin (ED50 = 11.38 mg/kg). Molecular docking and molecular dynamics studies also showed that compound a4 binds strongly to the ribosomal peptidyl transferase center (PTC), a key target for pleuromutilin derivatives. These results suggest that compound a4, with its enhanced antibacterial activity and low resistance potential, is a promising candidate for further development as an effective treatment for MRSA infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The growing prevalence of microbial infections, and antimicrobial resistance (AMR) stemming from the overuse and misuse of antibiotics, call for novel therapeutic agents, particularly ones targeting resistant microbial strains. Scientists are striving to develop innovative agents to tackle the rising microbial infections and abate the risk of AMR. Pyrazole, a five-membered heterocyclic compound belonging to the azole family, is a versatile scaffold and serves as a core structure in many drugs with antimicrobial and other therapeutic effects. In this review, we have updated pyrazole-based antibacterial and antifungal agents mainly developed between 2016 and 2024, by combining with diverse pharmacophores such as coumarin, thiazole, oxadiazole, isoxazole, indole, etc. Meanwhile, the various strategies (molecular hybridization, bioisosterism, scaffold hopping, multicomponent reactions, and catalyst-free synthesis) for integrating different functional groups with the pyrazole ring are discussed. Additionally, structure-activity relationships of these pyrazole derivatives, i.e., how structural modifications impact their selectivity and therapeutic potential against bacterial and fungal strains, are highlighted. This review provides insights into designing next-generation antimicrobials to combat AMR, and offers valuable perspectives to the scientists working on heterocyclic compounds with diverse bioactivities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Many widely used conventional antibiotics have failed to show clinical efficacy against Pseudomonas aeruginosa (P. aeruginosa) due to the strain's rising resistance to most clinically relevant antimicrobials. P. aeruginosa uses quorum sensing to regulate its virulence and biofilm development, which contributes to its pathogenicity and drug resistance. This mechanism is responsible for the resurgence and persistence of infections. Therefore, targeting the virulence and pathogenicity of P. aeruginosa through quorum sensing (QS) is regarded as a potential target for anti-infective therapy. However, a number of natural and synthetic compounds have been demonstrated to interfere with quorum sensing, resulting in potential antibacterial agents. In this review, we discuss the mechanisms of P. aeruginosa QS and recent advances in the development of quorum sensing inhibitors (both synthetic and natural) that have the potential to become effective antibiotics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multi-resistant organisms found in hospital-acquired infections and is associated with high morbidity and mortality. The development of new drugs and promising therapeutic strategies against MRSA is thus an urgent request. In recent years, some natural products have been demonstrated to show great potential in improving the efficacy of antibiotics to treat various drug-resistant bacteria, particularly MRSA. In this context, we aimed to analyze systematically from the prior arts that investigated the synergy between natural products and antibiotics against MRSA. These findings not only give us a better understanding on the mechanism of actions but also shed light on the bioactive molecular scaffolds identified from diverse natural products. In the present study, we concentratedly reviewed the studies that utilized natural products to enhance the potency of conventional antibiotics against MRSA in the last decade. The timely information reported herein may give meaningful insights into the molecular design of novel and potent antibacterial agents and/or effective therapeutics to combat MRSA for practical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)