Development of a luciferase-based Gram-positive bacterial reporter system for the characterization of antimicrobial agents.

Mechanistic investigations are of paramount importance in elucidating the modes of action of antibiotics and facilitating the discovery of novel drugs. We reported a luciferase-based reporter system using bacterial cells to unveil mechanisms of antimicrobials targeting transcription and translation. The reporter gene Nluc encoding NanoLuciferase (NanoLuc) was integrated into the genome of the Gram-positive model organism, Bacillus subtilis, to generate a reporter strain BS2019. Cellular transcription and translation levels were assessed by quantifying the amount of Nluc mRNA as well as the luminescence catalyzed by the enzyme NanoLuc. We validated this system using three known inhibitors of transcription (rifampicin), translation (chloramphenicol), and cell wall synthesis (ampicillin). The B. subtilis reporter strain BS2019 successfully revealed a decline in Nluc expression by rifampicin and NanoLuc enzyme activity by chloramphenicol, while ampicillin produced no observable effect. The assay was employed to characterize a previously discovered bacterial transcription inhibitor, CUHK242, with known antimicrobial activity against drug-resistant Staphylococcus aureus. Production of Nluc mRNA in our reporter BS2019 was suppressed in the presence of CUHK242, demonstrating the usefulness of the construct, which provides a simple way to study the mechanism of potential antibiotic candidates at early stages of drug discovery. The reporter system can also be modified by adopting different promoters and reporter genes to extend its scope of contribution to other fields of work. IMPORTANCE: Discovering new classes of antibiotics is desperately needed to combat the emergence of multidrug-resistant pathogens. To facilitate the drug discovery process, a simple cell-based assay for mechanistic studies is essential to characterize antimicrobial candidates. In this work, we developed a luciferase-based reporter system to quantify the transcriptional and translational effects of potential compounds and validated our system using two currently marketed drugs. Reporter strains generated in this study provide readily available means for identifying bacterial transcription inhibitors as prospective novel antibacterials. We also provided a series of plasmids for characterizing promoters under various conditions such as stress.

Screening of promising molecules against potential drug targets in Yersinia pestis by integrative pan and subtractive genomics, docking and simulation approach.

This study focuses on Yersinia pestis, the bacterium responsible for plague, which posed a severe threat to public health in history. Despite the availability of antibiotics treatment, the emergence of antibiotic resistance in this pathogen has increased challenges of controlling the infections and plague outbreaks. The development of new drug targets and therapies is urgently needed. This research aims to identify novel protein targets from 28 Y. pestis strains by the integrative pan-genomic and subtractive genomics approach. Additionally, it seeks to screen out potential safe and effective alternative therapies against these targets via high-throughput virtual screening. Targets should lack homology to human, gut microbiota, and known human 'anti-targets', while should exhibit essentiality for pathogen's survival and virulence, druggability, antibiotic resistance, and broad spectrum across multiple pathogenic bacteria. We identified two promising targets: the aminotransferase class I/class II domain-containing protein and 3-oxoacyl-[acyl-carrier-protein] synthase 2. These proteins were modeled using AlphaFold2, validated through several structural analyses, and were subjected to molecular docking and ADMET analysis. Molecular dynamics simulations determined the stability of the ligand-target complexes, providing potential therapeutic options against Y. pestis.

Cefepime-Enmetazobactam: A Drug Review of a Novel Beta-Lactam/Beta-Lactamase Inhibitor.

OBJECTIVE: To describe and analyze the pharmacodynamic and pharmacokinetic properties and clinical evidence supporting the efficacy and use of cefepime-enmetazobactam (FEP-EMT). DATA SOURCES: A literature search was conducted using MEDLINE and EMBASE databases (January 2015 to May 2024). Search terms included: "cefepime-enmetazobactam" or "cefepime" or "enmetazobactam" or "cefepime" or "novel beta-lactamase inhibitor" and "complicated urinary tract infection" or "cUTI." Conference abstracts, bibliographies, clinical trials, and drug monographs were included for review. STUDY SELECTION AND DATA EXTRACTION: Relevant studies in English and clinical trials conducted in humans were reviewed. DATA SYNTHESIS: In February 2024, the Food and Drug Administration (FDA) approved the combination beta-lactam/beta-lactamase inhibitor (BL/BLI) FEP-EMT for the treatment of complicated urinary tract infections (cUTIs) and acute pyelonephritis following the completion of the Phase III ALLIUM trial comparing it to piperacillin-tazobactam (TZP). The trial resulted in 79.1% of the FEP-EMT group versus 58.9% of the TZP group meeting the primary outcome of clinical cure and microbiological eradication (95% CI 21.2 [14.3 to 27.9]). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING AGENTS: This review describes the use of FEP-EMT for the treatment of cUTI and compares its use to other novel BL/BLI combinations including utility in drug-resistant infections. CONCLUSIONS: FEP-EMT provides an antimicrobial option to reduce overuse of carbapenems for extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. However, unlike other novel BL/BLI combinations, its limited spectrum of antibacterial effect for more difficult-to-treat pathogens and cost may also impact its overall utilization.

Secondary Metabolites from Marine-Derived Bacteria with Antibiotic and Antibiofilm Activities against Drug-Resistant Pathogens.

The search for new antibiotics against drug-resistant microbes has been expanded to marine bacteria. Marine bacteria have been proven to be a prolific source of a myriad of novel compounds with potential biological activities. Therefore, this review highlights novel and bioactive compounds from marine bacteria reported during the period of January 2016 to December 2021. Published articles containing novel marine bacterial secondary metabolites that are active against drug-resistant pathogens were collected. Previously described compounds (prior to January 2016) are not included in this review. Unreported compounds during this period that exhibited activity against pathogenic microbes were discussed and compared in order to find the cue of the structure-bioactivity relationship. The results showed that Streptomyces are the most studied bacteria with undescribed bioactive compounds, followed by other genera in the Actinobacteria. We have categorized the structures of the compounds in the present review into four groups, based on their biosynthetic origins, as polyketide derivatives, amino acid derivatives, terpenoids, as well as compounds with mixed origin. These compounds were active against one or more drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin-resistant Enterococci (VRE), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and amphotericin B-resistant Candida albicans. In addition, some of the compounds also showed activity against biofilm formation of the test bacteria. Some previously undescribed compounds, isolated from marine-derived bacteria during this period, could have a good potential as lead compounds for the development of drug candidates to overcome multidrug-resistant pathogens.

Genome insights into the pharmaceutical and plant growth promoting features of the novel species Nocardia alni sp. nov.

BACKGROUND: Recent studies highlighted the biosynthetic potential of nocardiae to produce diverse novel natural products comparable to that of Streptomyces, thereby making them an attractive source of new drug leads. Many of the 119 Nocardia validly named species were isolated from natural habitats but little is known about the diversity and the potential of the endophytic nocardiae of root nodule of actinorhizal plants. RESULTS: The taxonomic status of an actinobacterium strain, designated ncl2T, was established in a genome-based polyphasic study. The strain was Gram-stain-positive, produced substrate and aerial hyphae that fragmented into coccoid and rod-like elements and showed chemotaxonomic properties that were also typical of the genus Nocardia. It formed a distinct branch in the Nocardia 16S rRNA gene tree and was most closely related to the type strains of Nocardia nova (98.6%), Nocardia jiangxiensis (98.4%), Nocardia miyuensis (97.8%) and Nocardia vaccinii (97.7%). A comparison of the draft genome sequence generated for the isolate with the whole genome sequences of its closest phylogenetic neighbours showed that it was most closely related to the N. jiangxiensis, N. miyuensis and N. vaccinii strains, a result underpinned by average nucleotide identity and digital DNA-DNA hybridization data. Corresponding taxogenomic data, including those from a pan-genome sequence analysis showed that strain ncl2T was most closely related to N. vaccinii DSM 43285T. A combination of genomic, genotypic and phenotypic data distinguished these strains from one another. Consequently, it is proposed that strain ncl2T (= DSM 110931T = CECT 30122T) represents a new species within the genus Nocardia, namely Nocardia alni sp. nov. The genomes of the N. alni and N. vaccinii strains contained 36 and 29 natural product-biosynthetic gene clusters, respectively, many of which were predicted to encode for a broad range of novel specialised products, notably antibiotics. Genome mining of the N. alni strain and the type strains of its closest phylogenetic neighbours revealed the presence of genes associated with direct and indirect mechanisms that promote plant growth. The core genomes of these strains mainly consisted of genes involved in amino acid transport and metabolism, energy production and conversion and transcription. CONCLUSIONS: Our genome-based taxonomic study showed that isolate ncl2T formed a new centre of evolutionary variation within the genus Nocardia. This novel endophytic strain contained natural product biosynthetic gene clusters predicted to synthesize novel specialised products, notably antibiotics and genes associated with the expression of plant growth promoting compounds.

Use of elicitors to enhance or activate the antibiotic production in streptomyces.

Streptomyces is the largest and most significant genus of Actinobacteria, comprising 961 species. These Gram-positive bacteria produce many versatile and important bioactive compounds; of these, antibiotics, specifically the enhancement or activation of their production, have received extensive research attention. Recently, various biotic and abiotic elicitors have been reported to modify the antibiotic metabolism of Streptomyces, which promotes the production of new antibiotics and bioactive metabolites for improvement in the yields of endogenous products. However, some elicitors that obviously contribute to secondary metabolite production have not yet received sufficient attention. In this study, we have reviewed the functions and mechanisms of chemicals, novel microbial metabolic elicitors, microbial interactions, enzymes, enzyme inhibitors, environmental factors, and novel combination methods regarding antibiotic production in Streptomyces. This review has aimed to identify potentially valuable elicitors for stimulating the production of latent antibiotics or enhancing the synthesis of subsistent antibiotics in Streptomyces. Future applications and challenges in the discovery of new antibiotics and enhancement of existing antibiotic production using elicitors are discussed.

Antibiotics in the pipeline: a literature review (2017-2020).

INTRODUCTION: Antimicrobial resistance (AMR) is an emerging global threat. It increases mortality and morbidity and strains healthcare systems. Health care professionals can counter the rising AMR by promoting antibiotic stewardship and facilitating new drug development. Even with the economic and scientific challenges, it is reassuring that new agents continue to be developed. METHODS: This review addresses new antibiotics in the pipeline. We conducted a review of the literature including Medline, Clinicaltrials.org, and relevant pharmaceutical companies for approved and in pipeline antibiotics in phase 3 or new drug application (NDA). RESULTS: We found a number of new antibiotics and reviewed their current development status, mode of action, spectra of activity, and indications for which they have been approved. The included studies from phase 3 clinical trials were mainly utilized for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and pneumonia acquired in the healthcare settings. The number of these agents is limited against high priority organisms. The identified antibiotics were based mainly on previously known molecules or pre-existing antimicrobial agents. CONCLUSION: There are a limited number of antibiotics against high priority organisms such as multi-drug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae. New antimicrobial agents directed against the top priority organisms as classified by the World Health Organization are urgently needed.

Assessment of Data Supporting the Efficacy of New Antibiotics for Treating Infections Caused by Multidrug-resistant Bacteria.

BACKGROUND: Infections caused by multidrug-resistant (MDR) bacteria are a major public health threat. We aimed to assess the data supporting US Food and Drug Administration (FDA) approval of new agents aimed to treat MDR bacterial infections and the data provided by postmarketing studies. METHODS: We identified all drugs with in vitro activity against MDR bacteria initially approved by the FDA between January 2010 and December 2018. Characteristics of trials supporting approval and regulatory pathways were collected from Drugs@FDA. Characteristics of postmarketing studies were extracted from drug labels and ClinicalTrials.gov entries effective 1 June 2019. RESULTS: Initial approval of 11 newly approved antibiotics with anti-MDR activity was supported by 20 trials, all with noninferiority design. All initially approved indications were for common infections, mostly acute bacterial skin and skin-structure infections, regardless of causative microorganism. The proportion of MDR bacteria in most trials was low (<10% for gram-negative infections, <1% for gram-positive pneumonia). Most trials (90%) excluded immunocompromised and critically ill patients. Of 16 additional postmarketing randomized controlled trials identified through ClinicalTrials.gov, only 2 exclusively included infections caused by MDR bacteria, comprising 116 patients. No drug was granted accelerated approval, which would mandate postmarketing efficacy studies. CONCLUSIONS: The approval of new drugs with potential clinical activity against MDR bacteria is supported by trials evaluating infections caused by non-MDR organisms, using noninferiority design and excluding the patients most likely to require these agents. Subsequent postmarketing efficacy data against these organisms are scarce. Healthcare professionals and regulators should demand more robust data to support clinical decision making.

Extensively Drug-Resistant Acinetobacter baumannii Nosocomial Pneumonia Successfully Treated with a Novel Antibiotic Combination.

Extremely drug-resistant (XDR) Acinetobacter baumannii causes challenging nosocomial infections. We report the case of a patient with XDR A. baumannii pneumonia and septic shock successfully treated with cefiderocol and a novel antibiotic obtained via expanded access protocol. With focused research and drug development efforts, the poor outcomes associated with these infections may be mitigated.

Mining Indonesian Microbial Biodiversity for Novel Natural Compounds by a Combined Genome Mining and Molecular Networking Approach.

Indonesia is one of the most biodiverse countries in the world and a promising resource for novel natural compound producers. Actinomycetes produce about two thirds of all clinically used antibiotics. Thus, exploiting Indonesia's microbial diversity for actinomycetes may lead to the discovery of novel antibiotics. A total of 422 actinomycete strains were isolated from three different unique areas in Indonesia and tested for their antimicrobial activity. Nine potent bioactive strains were prioritized for further drug screening approaches. The nine strains were cultivated in different solid and liquid media, and a combination of genome mining analysis and mass spectrometry (MS)-based molecular networking was employed to identify potential novel compounds. By correlating secondary metabolite gene cluster data with MS-based molecular networking results, we identified several gene cluster-encoded biosynthetic products from the nine strains, including naphthyridinomycin, amicetin, echinomycin, tirandamycin, antimycin, and desferrioxamine B. Moreover, 16 putative ion clusters and numerous gene clusters were detected that could not be associated with any known compound, indicating that the strains can produce novel secondary metabolites. Our results demonstrate that sampling of actinomycetes from unique and biodiversity-rich habitats, such as Indonesia, along with a combination of gene cluster networking and molecular networking approaches, accelerates natural product identification.

Ribosome Protection Proteins-"New" Players in the Global Arms Race with Antibiotic-Resistant Pathogens.

Bacteria have evolved an array of mechanisms enabling them to resist the inhibitory effect of antibiotics, a significant proportion of which target the ribosome. Indeed, resistance mechanisms have been identified for nearly every antibiotic that is currently used in clinical practice. With the ever-increasing list of multi-drug-resistant pathogens and very few novel antibiotics in the pharmaceutical pipeline, treatable infections are likely to become life-threatening once again. Most of the prevalent resistance mechanisms are well understood and their clinical significance is recognized. In contrast, ribosome protection protein-mediated resistance has flown under the radar for a long time and has been considered a minor factor in the clinical setting. Not until the recent discovery of the ATP-binding cassette family F protein-mediated resistance in an extensive list of human pathogens has the significance of ribosome protection proteins been truly appreciated. Understanding the underlying resistance mechanism has the potential to guide the development of novel therapeutic approaches to evade or overcome the resistance. In this review, we discuss the latest developments regarding ribosome protection proteins focusing on the current antimicrobial arsenal and pharmaceutical pipeline as well as potential implications for the future of fighting bacterial infections in the time of "superbugs."

Antibiotic-Potentiating Activity of Phanostenine Isolated from Cissampelos sympodialis Eichler.

Cissampelos sympodialis Eichler is well studied and investigated for its antiasthmatic properties, but there are no data in the literature describing antibacterial properties of alkaloids isolated from this botanical species. This work reports the isolation and characterization of phanostenine obtained from roots of C. sympodialis and describes for the first time its antimicrobial and antibiotic modulatory properties. Phanostenine was first isolated from Cissampelos sympodialis and its antibacterial activities were determined. Chemical structures of the alkaloid isolate were determined using spectroscopic and chemical analyses. Phanostenine was also tested for its antibacterial activity against standard strains and clinical isolates of Escherichia coli and Staphylococcus aureus. Minimal inhibitory concentration (MIC) was determined in a microdilution assay and for the evaluation of antibiotic resistance-modifying activity. MIC of the antibiotics was determined in the presence or absence of phanostenine at sub-inhibitory concentrations. The evaluation of antibacterial activity by microdilution assay showed activity for all strains with better values against S. aureus ATCC 12692 and E. coli 27 (787.69 mm). The evaluation of aminoglycoside antibiotic resistance-modifying activity showed reduction in the MIC of the aminoglycosides (amikacin, gentamicin and neomycin) when associated with phanostenine, MIC reduction of antibiotics ranging from 21 % to 80 %. The data demonstrated that phanostenine possesses a relevant ability to modify the antibiotic activity in vitro. We can suggest that phanostenine presents itself as a promising tool as an adjuvant for novel antibiotics formulations against bacterial resistance.

Antibiotic discovery: combining isolation chip (iChip) technology and co-culture technique.

Antibiotics had been a useful tool for treating bacterial infections since their discovery, but with the passage of time, the evolution of resistance among microbes against antibiotics has rendered them useless. Many approaches are being used to tackle this problem which include discovery of new antibiotics, modification of the existing ones, and elucidating mechanisms of resistance in microbes for a better understanding. In this review, we have discussed that discovery of new antibiotics is a basic need to fight emerging infectious bacteria, and for this purpose, we should target those microbes from the environment which are not easily culturable. For this purpose, culturing technique should be modified to the in situ culturing as nutritional requirements of unculturable bacteria are unknown. Two different cultivation strategies, diffusion chambers and iChip technology, have been reviewed for their excellent improvement in culturing compared to conventional techniques. Since co-culture is also an important factor which can result in exploring new microbial diversity, we hypothesize that if iChip and co-culture can be combined in a single device, it can allow production of novel antibiotics from those bacteria which are difficult to be cultured in the future.

Intracellular Targeting Mechanisms by Antimicrobial Peptides.

Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.

Looking for the new preparations for antibacterial therapy. V. New antimicrobial agents from the oxazolidinones groups in clinical trials

This paper is the fifth part of the series concerning the search for new preparations for antibacterial therapy and discussing new compounds belonging to the oxazolidinone class of antibacterial chemotherapeutics. This article presents five new substances that are currently at the stage of clinical trials (radezolid, sutezolid, posizolid, LCB01-0371 and MRX-I). The intensive search for new antibiotics and antibacterial chemotherapeutics with effective antibacterial activity is aimed at overcoming the existing resistance mechanisms in order to effectively fight against multidrug-resistant bacteria, which pose a real threat to public health. The crisis of antibiotic resistance can be overcome by the proper use of these drugs, based on bacteriological and pharmacological knowledge. Oxazolidinones, with their unique mechanism of action and favorable pharmacokinetic and pharmacodynamic parameters, represent an alternative way to effectively treat serious infections caused by Gram-positive microorganisms.

In Vitro Antimicrobial Activity of Five Newly Approved Antibiotics against Carbapenemase-Producing Enterobacteria-A Pilot Study in Bulgaria.

To solve the problem with pan-drug resistant and extensively drug-resistant Gram-negative microbes, newly approved drugs such as ceftazidime/avibactam, cefiderocol, plazomicin, meropenem/vaborbactam, and eravacycline have been introduced in practice. The aim of the present study was to collect carbapenemase-producing clinical Enterobacterales isolates, to characterize their carbapenemase genes and clonal relatedness, and to detect their susceptibility to commonly used antimicrobials and the above-mentioned newly approved antibiotics. Sixty-four carbapenemase producers were collected in a period of one year from four Bulgarian hospitals, mainly including Klebsiella pneumoniae (89% of the isolates) and also single Proteus mirabilis, Providencia stuartii and Citrobacter freundii isolates. The main genotype was blaNDM-1 (in 61%), followed by blaKPC-2 (23%), blaVIM-1 (7.8%) and blaOXA-48 (7.8%). Many isolates showed the presence of ESBL (blaCTX-M-15/-3 in 76.6%) and AmpC (blaCMY-4 in 37.5% or blaCMY-99 in 7.8% of isolates). The most common MLST type was K. pneumoniae ST11 (57.8%), followed by ST340 (12.5%), ST258 (6.3%) and ST101 (6.3%). The isolates were highly resistant to standard-group antibiotics, except they were susceptible to tigecycline (83.1%), colistin (79.7%), fosfomycin (32.8%), and aminoglycosides (20.3-35.9%). Among the newly approved compounds, plazomicin (90.6%) and eravacycline (76.3%) showed the best activity. Susceptibility to ceftazidime/avibactam and meropenem/vaborbactam was 34.4% and 27.6%, respectively. For cefiderocol, a large discrepancy was observed between the percentages of susceptible isolates according to EUCAST susceptibility breakpoints (37.5%) and those of CLSI (71.8%), detected by the disk diffusion method. This study is the first report to show patterns of susceptibility to five newly approved antibiotics among molecularly characterized isolates in Bulgaria. The data may contribute to both the improvement of treatment of individual patients and the choice of infection control strategy and antibiotic policy.

MultiRapid ATB NP test for detecting concomitant susceptibility and resistance of last-resort novel antibiotics available to treat multidrug-resistant Enterobacterales infections.

BACKGROUND: Recently developed therapeutics against Gram-negative bacteria include the ß-lactam-ß-lactamase inhibitor combinations ceftazidime-avibactam (CZA), meropenem-vaborbactam (MEV), and imipenem-relebatam (IPR), and the siderophore cephalosporin cefiderocol (FDC). The aim of this study was to develop a test for rapid identification of susceptibility/resistance to CZA, MEV, IPR, and FDC for Enterobacterales in a single test for rapid clinical decision making. METHODS: The MultiRapid ATB NP test is based on the detection of glucose metabolism occurring after bacterial growth in the presence of defined concentrations of CZA, MEV, IPR, and FDC, followed by visual detection of colour change of the pH indicator red phenol (red to yellow) generated by the acidification of the medium upon bacterial growth. This test is performed in 96-well microplates. The MultiRapid ATB NP test was evaluated using 78 Enterobacterales isolates and compared to the reference method broth microdilution. RESULTS: The MultiRapid ATB NP test displayed 97.0% (confidence interval [CI] 92.6-98.8) sensitivity, 97.7% (CI 94.3-99.1) specificity, and 97.4% (CI 95.0-98.7) accuracy. The results were obtained after 3 h of incubation at 35 °C ± 2 °C, representing at least a 15-h gain-of-time compared with currently used antimicrobial susceptibility testing methods. CONCLUSION: The MultiRapid ATB NP test provided accurate results for the concomitant detection of susceptibility/resistance to CZA, MEV, IPR, and FDC in Enterobacterales, independent of the resistance mechanism. This test may be suitable for implementation in any microbiology routine laboratory.

Acne treatment: research progress and new perspectives.

Acne is a chronic inflammatory skin disease that primarily affects adolescents and is attributed to various factors, including hormonal changes, genetic predisposition, and environmental influences. It typically manifests in areas rich in sebaceous glands such as the face, chest, and back. Symptoms of acne can range from mild to severe and may present as pimples, pustules, nodules, cysts, and scarring. The appearance of acne can significantly impact both the physical and mental well-being of patients, potentially leading to feelings of anxiety, depression, and social withdrawal. The pathogenesis of acne is multifaceted involving genetic predisposition as well as environmental factors such as hormonal imbalances, inflammation, abnormal follicular sebaceous unit keratinization, proliferation of follicular microorganisms like Propionibacterium acnes, increased sebum production, and dietary influences. Traditional treatment methods for acne include topical drug therapy, oral drug therapy, photoelectric therapy, and chemical peeling. With ongoing research into the pathogenesis of acne, treatment methods are rapidly evolving with novel antibiotics, probiotics, biological agents, topical anti-androgen drugs, topical vitamin A acid metabolism blockers, antimicrobial peptides, immunotherapy, micro-needling, and micro-needling patches. This article aims to provide a comprehensive review of recent advancements in acne treatment.

Multi-resistant organisms in burn patients: an end or a new beginning.

Infections are a major cause of morbidity and mortality in burn patients, and the rise of multidrug-resistant organisms (MDROs) has made it more challenging to manage and prevent infections. This review examines the available treatment options for MDROs in burn patients and anticipates the future challenges posed by their increasing prevalence. The review covers new antibiotics, such as Eravacycline and Plazomicin, as well as non-antibiotic therapies, such as bacteriophages and nanoparticles. Future research should focus on examining the long-term efficacy, cost-effectiveness, and in vivo efficacy of different treatment modalities. The potential of alternative therapies, such as probiotics and low-frequency magnetic fields, should also be explored. Accurate and rapid diagnostic and monitoring tools for detecting MDROs in burn patients should be developed. The emergence of MDROs in burn care is a challenge and a new beginning in infection innovation and novel treatments.

Crystallographic fragment screen of the c-di-AMP-synthesizing enzyme CdaA from Bacillus subtilis.

Crystallographic fragment screening has become a pivotal technique in structure-based drug design, particularly for bacterial targets with a crucial role in infectious disease mechanisms. The enzyme CdaA, which synthesizes an essential second messenger cyclic di-AMP (c-di-AMP) in many pathogenic bacteria, has emerged as a promising candidate for the development of novel antibiotics. To identify crystals suitable for fragment screening, CdaA enzymes from Streptococcus pneumoniae, Bacillus subtilis and Enterococcus faecium were purified and crystallized. Crystals of B. subtilis CdaA, which diffracted to the highest resolution of 1.1 Å, were used to perform the screening of 96 fragments, yielding data sets with resolutions spanning from 1.08 to 1.87 Å. A total of 24 structural hits across eight different sites were identified. Four fragments bind to regions that are highly conserved among pathogenic bacteria, specifically the active site (three fragments) and the dimerization interface (one fragment). The coordinates of the three active-site fragments were used to perform an in silico drug-repurposing screen using the OpenEye suite and the DrugBank database. This screen identified tenofovir, an approved drug, that is predicted to interact with the ATP-binding region of CdaA. Its inhibitory potential against pathogenic E. faecium CdaA has been confirmed by ITC measurements. These findings not only demonstrate the feasibility of this approach for identifying lead compounds for the design of novel antibacterial agents, but also pave the way for further fragment-based lead-optimization efforts targeting CdaA.