A Double-Edged Sword: Thioxanthenes Act on Both the Mind and the Microbiome

The rising tide of antibacterial drug resistance has given rise to the virtual elimination of numerous erstwhile antibiotics, intensifying the urgent demand for novel agents. A number of drugs have been found to possess potent antimicrobial action during the past several years and have the potential to supplement or even replace the antibiotics. Many of these ‘non-antibiotics’, as they are referred to, belong to the widely used class of neuroleptics, the phenothiazines. Another chemically and pharmacologically related class is the thioxanthenes, differing in that the aromatic N of the central phenothiazine ring has been replaced by a C atom. Such “carbon-analogues” were primarily synthesized with the hope that these would be devoid of some of the toxic effects of phenothiazines. Intensive studies on syntheses, as well as chemical and pharmacological properties of thioxanthenes, were initiated in the late 1950s. Although a rather close parallelism with respect to structure activity relationships could be observed between phenothiazines and thioxanthenes; several thioxanthenes were synthesized in pharmaceutical industries and applied for human use as neuroleptics. Antibacterial activities of thioxanthenes came to be recognized in the early 1980s in Europe. During the following years, many of these drugs were found not only to be antibacterial agents but also to possess anti-mycobacterial, antiviral (including anti-HIV and anti-SARS-CoV-2) and anti-parasitic properties. Thus, this group of drugs, which has an inhibitory effect on the growth of a wide variety of microorganisms, needs to be explored for syntheses of novel antimicrobial agents. The purpose of this review is to summarize the neuroleptic and antimicrobial properties of this exciting group of bioactive molecules with a goal of identifying potential structures worthy of future exploration.

Discovery and Development of Antibacterial Agents: Fortuitous and Designed

Today, antibacterial drug resistance has turned into a significant public health issue. Repeated intake, suboptimal and/or unnecessary use of antibiotics, and, additionally, the transfer of resistance genes are the critical elements that make microorganisms resistant to conventional antibiotics. A substantial number of antibacterials that were successfully utilized earlier for prophylaxis and therapeutic purposes have been rendered inadequate due to this phenomenon. Therefore, the exploration of new molecules has become a continuous endeavour. Many such molecules are at various stages of investigation. A surprisingly high number of new molecules are currently in the stage of phase 3 clinical trials. A few new agents have been commercialized in the last decade. These include solithromycin, plazomicin, lefamulin, omadacycline, eravacycline, delafloxacin, zabofloxacin, finafloxacin, nemonoxacin, gepotidacin, zoliflodacin, cefiderocol, BAL30072, avycaz, zerbaxa, vabomere, relebactam, tedizolid, cadazolid, sutezolid, triclosan and afabiacin. This article aims to review the investigational and recently approved antibacterials with a focus on their structure, mechanisms of action/resistance, and spectrum of activity. Delving deep, their success or otherwise in various phases of clinical trials is also discussed while attributing the same to various causal factors.

Evolution of antimicrobial resistance in departments with high risk of cross infections in Tunisia

Background Antimicrobial resistance is actually a real and ever-changing public health problem. The microbiology laboratory plays a key role to achieve collaboration with clinical services and the prevention and control of infection team. Objective Describe the bacterial ecology of departments with high risk of Health care associated infections and analyze the evolution of antimicrobial resistance. Methods A descriptive and retrospective study was carried out in the university hospital Sahloul. It concerned all strains isolated in departments with high risk of Health care associated infections. The study period was spread over 7 years from January 1st, 2010 to December 31th, 2016. Results A total of 6108 non-redundant bacterial strains were isolated. Isolated pathogens were mainly from the urology departement (n-2651, 43.4%).The most frequent isolated pathogens were Escherichia coli (n = 1329, 21,8%), K. pneumoniae (n = 992, 16,2%), and Acinetobacter baumannii (n = 763, 12,5%). Concerning these main isolated species, significant statistical differences were noticed in bacterial resistance evolution over the years. With E. coli, the evolution was essentially represented by an increase of amoxicillin, amoxicillin clavulanic, cefotaxime, gentamicin, and fluoroquinolones resistance. With K. pneumoniae, cefotaxime resistance was stable, however resistance to imipenem and gentamicin was increasing. There was also a significant increase in fluoroquinolone and aminoside resistance. With S. Aureus, an increase in methicillin resistance was detected from 11.1% in 2010 to 20% in 2016. Conclusions Antibacterial Drug Resistance is a dynamic and rapidly evolving phenomenon in our hospital. The most common MDR bacteria studied were enterobacteriaceae producing carbapenemase. The emergence of glycopeptid resistance in enterococci must be controlled in order to prevent its spread to the community and the transfer of staphylococcus resistance genes. Key messages Antibacterial Drug Resistance is a dynamic and rapidly evolving phenomenon in our hospital. The most common multi drug resistant bacteria studied were enterobacteriaceae producing carbapenemase.

Mitigating the Impact of Antibacterial Drug Resistance through Host-Directed Therapies: Current Progress, Outlook, and Challenges

ABSTRACT Increasing incidences of multidrug resistance in pathogenic bacteria threaten our ability to treat and manage bacterial infection. The development and FDA approval of novel antibiotics have slowed over the past decade; therefore, the adoption and improvement of alternative therapeutic strategies are critical for addressing the threat posed by multidrug-resistant bacteria. Host-directed therapies utilize small-molecule drugs and proteins to alter the host response to pathogen infection. Here, we highlight strategies for modulating the host inflammatory response to enhance bacterial clearance, small-molecule potentiation of innate immunity, and targeting of host factors that are exploited by pathogen virulence factors. Application of state-of-the-art “omic” technologies, including proteomics, transcriptomics, and image-omics (image-based high-throughput phenotypic screening), combined with powerful bioinformatics tools will enable the modeling of key signaling pathways in the host-pathogen interplay and aid in the identification of host proteins for therapeutic targeting and the discovery of host-directed small molecules that will regulate bacterial infection. We conclude with an outlook on research needed to overcome the challenges associated with transitioning host-directed therapies into a clinical setting.

Daptomycin-resistant Staphylococcus pettenkoferi of human origin.

The importance of nosocomial infections caused by coagulase-negative staphylococci is constantly growing. The threat primarily affects immunocompromised patients, the elderly and neonates, particularly after invasive surgery. The problem is fundamentally exacerbated by expanding antibacterial drug resistance. A case report is presented of an 86-year-old patient who underwent a ruptured abdominal aortic aneurysm surgery and developed septicaemia upon surgical wound infection. The causal agent was likely a carbapenem-resistant Klebsiella pneumoniae, however, daptomycin-resistant Staphylococcus pettenkoferi was identified in blood cultures in the absence of daptomycin treatment. To the authors' knowledge, the case study presented is the first published episode of daptomycin-resistant S. pettenkoferi strain.