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Novel substituted monohydrazides synthesized for this study displayed broad-spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains. The activity of these compounds was either comparable or superior to amphotericin B against most of the fungal strains tested. These compounds possessed fungistatic activity in a time-kill assay and exhibited no mammalian cell toxicity. In addition, they prevented the formation of fungal biofilms. Even after repeated exposures, the Candida albicans ATCC 10231 (strain A) fungal strain did not develop resistance to these monohydrazides., Competing Interests: The authors have no conflict of interest to disclose., (This journal is © The Royal Society of Chemistry.)

Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn 2+ -dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus , one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus . Our results will inform future studies on inhibitor design for the FosB enzymes., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1 ), was a potent Eis inhibitor with IC 50 = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol ( 1 ) complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol ( 1 ), eight analogues, some of which were smaller than 1 , potently inhibited Eis (IC 50 ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant Mtb strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

Periodontal diseases, such as gingivitis and periodontitis, are inflammatory diseases triggered by pathogenic bacteria that lead to damage of the soft tissue and bone supporting the teeth. Amongst the identified oral periodontopathogenic bacteria, Porphyromonas gingivalis is able to enhance oral dysbiosis, which is an imbalance in the beneficial commensal and periodontal pathogenic bacteria that induces chronic inflammation. Given the critical role of oral pathogenic bacteria like P. gingivalis in the pathogenesis of periodontitis, local and/or systemic antibacterial therapy has been suggested to treat this disease, especially in its severe or refractory forms. Nevertheless, the majority of the antibacterial agents currently used for the treatment of periodontal diseases are broad-spectrum, which harms beneficial bacterial species that are critical in health, inhibit the growth of pathogenic bacteria, contribute in protecting the periodontal tissues to damage and aid in its healing. Thus, the development of more effective and specific antibacterial agents is needed to control oral pathogens in a polymicrobial environment. The strategies for the development of novel antibacterial agents include natural product isolation as well as synthetic and semi-synthetic methodologies. This review presents an overview of the periodontal diseases gingivitis and periodontitis along with current antibacterial treatment options ( i.e. , classes of antibacterial agents and the mechanism(s) of resistance that hinder their usage) used in periodontal diseases that specifically target oral pathogens such as P. gingivalis . In addition, to help medicinal chemists gain a better understanding of potentially promising scaffolds, this review provides an in-depth coverage of the various families of small molecules that have been investigated as potential anti- P. gingivalis agents, including novel families of compounds, repositioned drugs, as well as natural products., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Substance use disorders are diseases of the brain that create a dependency on drug(s), either prescription or illicit. These diseases affect millions of people worldwide, yet, there are few treatments that can help patients in the long term. This opinion piece looks at strategies researchers and institutes are taking to help find treatments as well as at new therapies in clinical trials. It provides an outlook on how a changing public perspective of these diseases can ultimately lead to a brighter outlook for substance use disorder treatments., (This journal is © The Royal Society of Chemistry 2020.)