Development Of Antibiotics Research Articles

Decreased susceptibility to viscosin in Streptococcus pneumoniae.

Growing numbers of infections caused by antibiotic-resistant Streptococcus pneumoniae strains are a major concern for healthcare systems that will require new antibiotics for treatment as well as preventative measures that reduce the number of infections. Lipopeptides are antimicrobial molecules, of which some are used as antibiotics, including the last resort antibiotics daptomycin and polymyxins. Here we have studied the antimicrobial effect of the cyclic lipopeptide viscosin on S. pneumoniae growth and morphology. Most lipopeptides function as surfactants that create pores in membrane layers, which is regarded as their main antimicrobial activity. We show that viscosin can inhibit growth of S. pneumoniae without disintegration of the cytoplasmic membrane. Instead, the cells developed abnormal shapes and misplaced new division sites. The cell wall of these bacteria appeared less dense in electron microscopy images, suggesting that viscosin interfered with normal cell wall synthesis. Corroborating this observation, a luciferase reporter assay was used to show that the two-component systems LiaFSR and CiaRH, which are known to be activated upon cell wall stress, were strongly induced by viscosin. Furthermore, a mutant displaying 1.8-fold decreased susceptibility to viscosin was generated by sequential exposure to increasing concentrations of the lipopeptide. The mutant suffered from significant fitness loss and had mutations in genes involved in fatty acid synthesis, teichoic acid synthesis, and cell wall synthesis as well as transcription and translation. How these mutations might be linked to decreased viscosin susceptibility is discussed.IMPORTANCEStreptococcus pneumoniae is a leading cause of bacterial pneumonia, sepsis, and meningitis in children, and the incidence of infections caused by antibiotic-resistant strains is increasing. Development of new antibiotics is therefore necessary to treat these types of infections in the future. Here, we have studied the activity of the antimicrobial lipopeptide viscosin on S. pneumoniae and show that in addition to having the typical membrane destabilizing activity of lipopeptides, viscosin inhibits pneumococcal growth by obstructing normal cell wall synthesis. This suggests a more specific mode of action than just the surfactant activity. Furthermore, we show that S. pneumoniae does not easily acquire resistance to viscosin, which makes it a promising molecule to explore further, for example, by synthesizing less toxic derivates that can be tested for therapeutic potential.

A Review on Environmental Impacts and Risks of Beneficial Microorganisms

The diverse realm of microorganisms, including bacteria, Achaea, fungi, protists, and viruses, plays a crucial role in supporting life on Earth. Microbes are present in various environments, such as Arctic regions and thermal vents, where they participate in vital functions like nutrient cycling, soil formation, pollutant decomposition, and symbiotic interactions with plants. Their positive effects on soil quality, plant development, and animal well-being are a result of their metabolic processes, relationships with other organisms, and utilization in different applications. While beneficial microorganisms present opportunities for improving agriculture, bioremediation, genetic modification, and sustainable biotechnology practices, safety concerns must be addressed. In agriculture, beneficial microorganisms are employed as biopesticides to reduce the use of chemical pesticides, although potential impacts on non-target species need to be considered. Bioremediation, an environmentally friendly method that uses living organisms to break down pollutants, offers benefits with minimal harm to the environment. Nonetheless, challenges such as effectiveness in extreme conditions and the risk of incomplete degradation or unintended ecological disturbances remain significant. Wastewater treatment harnesses beneficial microorganisms to degrade pollutants, leading to reduced chemical usage and the promotion of energy-efficient processes like anaerobic digestion. Yet, issues related to antibiotic resistance development and incomplete remediation are raised. Genetic engineering presents environmental advantages through genetically modified microorganisms (GMMs), assisting in bioremediation, sustainable agriculture, waste management, and bioenergy generation. However, concerns arise regarding potential ecological disruptions caused by altered microbial populations and the dissemination of antibiotic resistance genes. Addressing environmental and safety risks associated with beneficial microorganisms necessitates comprehensive approaches, including thorough risk evaluations, implementation of containment strategies, assurance of ecological harmony, and contemplation of ethical and social consequences. This study aimed to investigate the environmental impacts and safety considerations involved in the application of beneficial microorganisms.

The antibiotic resistance crisis and the development of new antibiotics.

The Global Burden of Disease report of 2019 estimated 14 million infection-related deaths, making it the second leading cause of death after ischaemic heart disease. Bacterial pathogens accounted for 7.7 million deaths and deaths attributable to bacterial antibiotic resistance amounted to 1.3 million, describing a clear demand for novel antibiotics. Antibiotic development had its golden age in 1930-1960. Following failures in the screening of chemical libraries for novel antibiotics at the beginning of this century, the high cost of launching new antibiotics (estimated at US$ 1.4 billion per registered drug) and difficulties in achieving a return of investment for novel antibiotics, pharmaceutical industry has mostly left the field. The current Lilliput review analyses the question whether scientific or economic hurdles prevented the registration of new antibiotics. Scientifically, substantial progress has been achieved over recent years to define the chemical properties needed to overcome the permeation barrier in Gram-negative pathogens; in extending the chemical space of antibiotic candidates by full modular synthesis of suitable molecules; by extending bioprospecting to previously 'unculturable' bacteria or unusual bacteria; by attacking bacterial targets on the outer bacterial membrane; and by looking for support from structural biology, genomics, molecular genetics, phylogenetic analyses and deep machine learning approaches. However, these research activities were mostly conducted by academic researchers and biotech companies with limited financial resources. It thus seems that the development of new antibiotics, frequently described as the drying of the pipeline, is less limited by lack of scientific insight than by lack of the mobilization of the monetary resources needed to bring these discoveries to the market despite recent financial push and pull efforts of the public sector.

Evaluation of the Anti-MRSA Activity of Supercritical Carbon Dioxide and Macerated Crude Extracts of Padina spp. Collected from the Coastal Waters of Tacloban City, the Philippines

The World Health Organization classifies methicillin-resistant Staphylococcus aureus (MRSA) as a high priority in the pathogens list for research and development of new antibiotics. Natural compounds from brown algae are being studied for their potential as alternative sources of antibiotics, including Padina spp. This study aims to evaluate the anti-MRSA activity of the crude extracts obtained through supercritical carbon dioxide extraction (SCCO2) and maceration (MAC) of Padina spp. seaweeds from the coastal waters of Tacloban City, the Philippines. The evaluation of extracts for their anti-MRSA and anti-MSSA (methicillin-susceptible Staphylococcus aureus) activities was done via the resazurin microplate assay, and the Mann-Whitney U test was used to compare these activities. Results show that MAC exhibited minimum inhibitory concentrations (MIC) of 2,048–4,096 μg/mL and 512–4,096 μg/mL for SCCO2 for the MRSA and MSSA control and clinical isolates, respectively. While the MICs for the SCCO2 extracts were lower than those for the MAC extracts, no significant difference was found between the MICs of the extracts from the two extraction methods. No significant difference was observed between the MICs of the extracts against the MRSA (43300) and MSSA (25923) ATCC strains and clinical isolates. Finally, significant differences were observed between the MICs of the control antibiotics and both extraction methods.

A study on viruses and bacteria with particular interest on Mycoplasma pneumoniae in children with exacerbation of asthma from a tertiary care hospital in Sri Lanka.

Asthma is a significant public health concern, particularly in children with severe symptoms. Exacerbation of asthma (EOA) is life-threatening, and respiratory infections (RIs) play a crucial role. Though viruses play a significant role in EOA, patients are empirically treated with antibiotics, contributing to antibiotic resistance development. Although there are widely reported associations of EOA with viral or Mycoplasma pneumoniae infections, there are no published data for Sri Lanka. The present study aimed to identify the association of common respiratory viruses, typical respiratory bacterial pathogens and M. pneumoniae in children with EOA and relate them with the compatibility of antimicrobial use. A case-control study was conducted in the paediatric unit of North Colombo Teaching Hospital, Sri Lanka, involving two groups of children between 5 and 15 years of age. Group 1 is children with EOA and Group 2 is children with stable asthma (SA). Each group consisted of 100 children. Sputum/throat swabs were tested for common respiratory viruses using virus-specific fluorescein isothiocyanate-labelled monoclonal antibodies (MAbs), bacteria by routine culture, and M. pneumoniae by real-time polymerase chain reaction. Macrolide resistance in M. pneumoniae was detected using conventional PCR and sequencing specific genetic mutations in the 23S rRNA gene. M. pneumoniae was genotyped using nested multilocus sequence typing, which targeted eight housekeeping genes (ppa, pgm, gyrB, gmk, glyA, atpA, arcC and adk). There was no significant difference in age, gender, demographic or geographical location between the two groups. In children with EOA, antibiotics were used in 66 % (66/100) and macrolides in 42 % (42/100). Samples comprised 78 % (78/100) sputum and 22 % (22/100) throat swabs. Adenovirus was the most common virus identified, and it was significantly higher in children with EOA compared to those with SA. Still, the two groups had no significant difference in typical bacteria findings. M. pneumoniae was detected in one patient with EOA, but none was detected in the SA group. The M. pneumoniae was macrolide-sensitive and ST14 by multilocus sequence typing. This study showed that the empiric use of antibiotics in children with asthma might be better targeted with prior pathogen screening to inform appropriate treatment to minimize antibiotic resistance.

Evolving resistance landscape in gram-negative pathogens: An update on β-lactam and β-lactam-inhibitor treatment combinations for carbapenem-resistant organisms.

Antibiotic resistance has become a global threat as it is continuously growing due to the evolution of β-lactamases diminishing the activity of classic β-lactam (BL) antibiotics. Recent antibiotic discovery and development efforts have led to the availability of β-lactamase inhibitors (BLIs) with activity against extended-spectrum β-lactamases as well as Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant organisms (CRO). Nevertheless, there is still a lack of drugs that target metallo-β-lactamases (MBL), which hydrolyze carbapenems efficiently, and oxacillinases (OXA) often present in carbapenem-resistant Acinetobacter baumannii. This review aims to provide a snapshot of microbiology, pharmacology, and clinical data for currently available BL/BLI treatment options as well as agents in late stage development for CRO harboring various β-lactamases including MBL and OXA-enzymes.

Demographic, clinical and molecular epidemiology of extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infections in Central Australia

We describe the demographics, clinical and molecular epidemiology of extended-spectrum β-lactamase (ESBL) Escherichia coli bloodstream infections (BSI) in Central Australia. All ESBL-producing E.coli bloodstream isolates from January 2018 to December 2020 were retrospectively identified. Demographic and clinical information was extracted by chart review. Whole-genome sequencing was performed for multi-locus sequence typing, antibiotic-resistance genes, and phylogenetic relationships. We identified 41 non-duplicate episodes of ESBL E.coli BSI. Median age was 55 years (IQR 47-63), 78% were female, 93% were Aboriginal, and half came from a remote community. Infections were predominantly urinary (68%, 28/41). In the 12 months prior, 70% (26/37) of identified patients had been hospitalised and 81% (30/37) prescribed antibiotics. Meropenem and piperacillin-tazobactam susceptibility was maintained in 100% and 95% of isolates, respectively. Co-resistance to non-β-lactam antibiotics was 32% to gentamicin, 61% to trimethoprim/sulfamethoxazole, and 68% to ciprofloxacin. For sequenced isolates, 41% (16/35) were sequence type 131 (ST131). Mean acquired antibiotic-resistance genes for each isolate was 12.3 (SD 3.1). Four isolates carried an OXA-1 gene. Only non-ST131 isolates carried AmpC and acquired quinolone-resistance genes. There was some evidence of clustering of closely related strains, but no evidence of community or healthcare admission overlap. ESBL rates are rapidly rising in Central Australia, which is a conducive environment for antibiotic resistance development (e.g., overcrowding, socioeconomic disadvantages, high healthcare exposure and high antibiotic use). Future research is required to explore resistance-transmission dynamics in this unique setting.

Subtask-Aware Representation Learning for Predicting Antibiotic Resistance Gene Properties via Gating-Controlled Mechanism.

The crisis of antibiotic resistance has become a significant global threat to human health. Understanding properties of antibiotic resistance genes (ARGs) is the first step to mitigate this issue. Although many methods have been proposed for predicting properties of ARGs, most of these methods focus only on predicting antibiotic classes, while ignoring other properties of ARGs, such as resistance mechanisms and transferability. However, acquiring all of these properties of ARGs can help researchers gain a more comprehensive understanding of the essence of antibiotic resistance, which will facilitate the development of antibiotics. In this paper, the task of predicting properties of ARGs is modeled as a multi-task learning problem, and an effective subtask-aware representation learning-based framework is proposed accordingly. More specifically, property-specific expert networks and shared expert networks are utilized respectively to learn subtask-specific features for each subtask and shared features among different subtasks. In addition, a gating-controlled mechanism is employed to dynamically allocate weights to subtask-specific semantics and shared semantics obtained respectively from property-specific expert networks and shared expert networks, thus adjusting distinctive contributions of subtask-specific features and shared features to achieve optimal performance for each subtask simultaneously. Extensive experiments are conducted on publicly available data, and experimental results demonstrate the effectiveness of the proposed framework on the task of ARGs properties prediction.

Applying Machine Learning for Antibiotic Development and Prediction of Microbial Resistance.

Antimicrobial resistance (AMR) poses a serious threat to human health worldwide. It is now more challenging than ever to introduce a potent antibiotic to the market considering rapid emergence of antimicrobial resistance, surpassing the rate of antibiotic drug discovery. Hence, new approaches need to be developed to accelerate the rate of drug discovery process and meet the demands for new antibiotics, while reducing the cost of their development. Machine learning holds immense promise of becoming a useful tool, especially since in the last two decades, exponential growth has occurred in computational power and biological big data analytics. Recent advancements in machine learning algorithms for drug discovery have provided significant clues for potential antibiotic classes. Apart from discovery of new scaffolds, the machine learning protocols will significantly impact prediction of AMR patterns and drug metabolism. In this review, we outline power of machine learning in antibiotic drug discovery, metabolic fate, and AMR prediction to support researchers engaged and interested in this field.

The Na+-translocating NADH:quinone oxidoreductase (Na+-NQR): Physiological role, structure and function of a redox-driven, molecular machine

Many bacterial processes are powered by the sodium motive force (smf) and in case of pathogens, the smf contributes to virulence. Vibrio cholerae, the causative agent of Cholera disease, possesses a Na+-translocating NADH:quinone oxidoreductase (NQR), a six-subunit membrane protein assembly. The 3D structure of NQR revealed the arrangement of the six subunits NqrABCDEF, the position of all redox cofactors (four flavins, two [2Fe-2S] centers) and the binding sites for the substrates NADH (in NqrF) and ubiquinone (in NqrB). Upon oxidation of NADH, electrons are shuttled twice across the membrane, starting with cytoplasmic FADNqrF and electron transfer to the [2Fe2S] clusterNqrF and from there to an intra-membranous [2Fe-2S] clusterNqrDE, periplasmic FMNNqrC, FMNNqrB and from there to riboflavinNqrB. This riboflavin is located at the cytoplasmic entry site of the sodium channel in NqrB, and it donates electrons to ubiquinone-8 positioned at the cytoplasmic side of NqrB. Targeting the substrate binding sites of NQR is a promising strategy to identify new inhibitors against many bacterial pathogens. Detailed structural information on the binding mode of natural inhibitors and small molecules in the active sites of NQR is now available, paving the way for the development of new antibiotics. The NQR shows different conformations as revealed in recent cryo-EM and crystallographic studies combined with spectroscopic analyses. These conformations represent distinct steps in the catalytic cycle. Considering the structural and functional data available, we propose a mechanism of Na+-NQR based on conformational coupling of electron transfer and Na+ translocation reaction steps.

Application of a pm-rf-APGD-type plasma brush for deactivation of antibiotics from liquid solutions leads to impaired development of drug resistance by bacterial pathogens

The presence of antibiotics residuals in the natural environment contributes to development and spread of drug resistance determinants among bacteria, often including clinically significant human pathogens. To tackle with this threat, we constructed a plasma brush, generating pulse-modulated radio-frequency atmospheric pressure glow discharge (pm-rf-APGD), named pm-rf-APGD-type plasma brush, intended for degradation of biologically active pharmaceuticals from both single- and five-component solutions of ciprofloxacin (CFX), enrofloxacin (EFX), ofloxacin (OFX), doxycycline (DXC), and trimethoprim (TMP). The mean antibiotics removal efficiency, achieved mainly due to the action of reactive oxygen species (ROS), was 93.3 %. This removal efficiency corresponded to a mean 62.7% decrease in the antibacterial activities. We revealed the transformation products resulting from an oxygen attack and/or internal fragmentation of the treated pharmaceuticals. Based on a laboratory evolution study, bacterial exposure to the pm-rf-APGD-treated drug lead to significantly lower rates of antibiotic resistance development in juxtaposition with a long-term exposure to the sublethal dose of the active molecules. Thus, we anticipate a great potential of high-throughput, continuous flow, eco-friendly pm-rf-APGD-type plasma brush for routine decontamination processes in the future disposal pipelines of pharmaceuticals-containing wastewaters.

Mining biosynthetic gene clusters in Paenibacillus genomes to discover novel antibiotics

BackgroundBacterial antimicrobial resistance poses a severe threat to humanity, necessitating the urgent development of new antibiotics. Recent advances in genome sequencing offer new avenues for antibiotic discovery. Paenibacillus genomes encompass a considerable array of antibiotic biosynthetic gene clusters (BGCs), rendering these species as good candidates for genome-driven novel antibiotic exploration. Nevertheless, BGCs within Paenibacillus genomes have not been extensively studied.ResultsWe conducted an analysis of 554 Paenibacillus genome sequences, sourced from the National Center for Biotechnology Information database, with a focused investigation involving 89 of these genomes via antiSMASH. Our analysis unearthed a total of 848 BGCs, of which 716 (84.4%) were classified as unknown. From the initial pool of 554 Paenibacillus strains, we selected 26 available in culture collections for an in-depth evaluation. Genomic scrutiny of these selected strains unveiled 255 BGCs, encoding non-ribosomal peptide synthetases, polyketide synthases, and bacteriocins, with 221 (86.7%) classified as unknown. Among these strains, 20 exhibited antimicrobial activity against the gram-positive bacterium Micrococcus luteus, yet only six strains displayed activity against the gram-negative bacterium Escherichia coli. We proceeded to focus on Paenibacillus brasilensis, which featured five new BGCs for further investigation. To facilitate detailed characterization, we constructed a mutant in which a single BGC encoding a novel antibiotic was activated while simultaneously inactivating multiple BGCs using a cytosine base editor (CBE). The novel antibiotic was found to be localized to the cell wall and demonstrated activity against both gram-positive bacteria and fungi. The chemical structure of the new antibiotic was elucidated on the basis of ESIMS, 1D and 2D NMR spectroscopic data. The novel compound, with a molecular weight of 926, was named bracidin.ConclusionsThis study outcome highlights the potential of Paenibacillus species as valuable sources for novel antibiotics. In addition, CBE-mediated dereplication of antibiotics proved to be a rapid and efficient method for characterizing novel antibiotics from Paenibacillus species, suggesting that it will greatly accelerate the genome-based development of new antibiotics.

Antibacterial activity and mechanisms of D-3263 against Staphylococcus aureus

Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane.

Microbiology of acute bacterial dacryocystitis: a tertiary institutional experience in South Australia

PurposeTo provide a comprehensive microbiological profile of bacterial dacryocystitis in South Australia. By identifying the specific microorganism and antibiotic susceptibility, this study intends to aid ophthalmologists in choosing appropriate empirical antibiotic therapies and development of evidence-based clinical guidelines.MethodA retrospective study was conducted at the Royal Adelaide Hospital (RAH) over five years (2018–2023) of patients with acute dacryocystitis. The study included 43 patients, and data encompassed demographic information, clinical presentation, microbiological analysis, management, and outcomes. Patients with chronic dacryocystitis were excluded.ResultsAmong the 43 patients included in the study (female 28 (65%), mean age: 64 years old), the most common clinical features were pain (74%) and swelling (70%). Organisms were identified in 49% of patients, with the predominant bacteria being Staphylococcus aureus (42%), Streptococcus species (19%), and Escherichia coli (8%). Aggregatibacter species (8%), Morganella morganii (4%), Enterobacter cloaceae (4%), Hafnia alvei (4%), mixed anaerobes (4%), E coliforms (4%) and Pseudomonas aeruginosa (4%) were also identified. The most frequently prescribed empirical antibiotics were amoxicillin-clavulanic acid (50%), flucloxacillin (33%) and cefalexin (18%).ConclusionThe microbiological trends of acute dacryocystitis have largely remained consistent, with a predominance of Gram positive organisms. This is the most recent profile analysis of acute dacryocystitis in South Australia and will help form evidence-based clinical guidelines.

Integration of molecular docking and molecular dynamics simulations with subtractive proteomics approach to identify the novel drug targets and their inhibitors in Streptococcus gallolyticus

Streptococcus gallolyticus (Sg) is a non-motile, gram-positive bacterium that causes infective endocarditis (inflammation of the heart lining). Because Sg has gained resistance to existing antibiotics and there is currently no drug available, developing effective anti-Sg drugs is critical. This study combined core proteomics with a subtractive proteomics technique to identify potential therapeutic targets for Sg. Several bioinformatics approaches were used to eliminate non-essential and human-specific homologous sequences from the bacterial proteome. Then, virulence, druggability, subcellular localization, and functional analyses were carried out to specify the participation of significant bacterial proteins in various cellular processes. The pathogen’s genome contained three druggable proteins, glucosamine-1phosphate N-acetyltransferase (GlmU), RNA polymerase sigma factor (RpoD), and pantetheine-phosphate adenylyltransferase (PPAT) which could serve as effective targets for developing novel drugs. 3D structures of target protein were modeled through Swiss Model. A natural product library containing 10,000 molecules from the LOTUS database was docked against therapeutic target proteins. Following an evaluation of the docking results using the glide gscore, the top 10 compounds docked against each protein receptor were chosen. LTS001632, LTS0243441, and LTS0236112 were the compounds that exhibited the highest binding affinities against GlmU, PPAT, and RpoD, respectively, among the compounds that were chosen. To augment the docking data, molecular dynamics simulations and MM-GBSA binding free energy were also utilized. More in-vitro research is necessary to transform these possible inhibitors into therapeutic drugs, though computer validations were employed in this study. This combination of computational techniques paves the way for targeted antibiotic development, which addresses the critical need for new therapeutic strategies against S. gallolyticus infections.

A panel of genotypically and phenotypically diverse clinical Acinetobacter baumannii strains for novel antibiotic development.

Acinetobacter baumannii is globally notorious, and in an effort to combat the spread of such pathogens, several emerging candidate therapies have already surfaced. However, the strains used to test these therapies vary across studies (the sources and numbers of test strains are varied and often very large, with little heterogeneity). The variation complicates the studies. Furthermore, the limited standardized resources of A. baumannii strains have greatly restricted the research on the physiology, pathogenicity, and antibiotic resistance. Therefore, it is crucial for the research community to acquire a standardized and heterogeneous panel of A. baumannii. Our study meticulously selected 45 diverse A. baumannii strains from a total of 2,197 clinical isolates collected from 64 different hospitals across 27 provinces in China, providing a scientific reference for the research community. This assistance will significantly facilitate scientific exchange in academic research.

Evolving Epidemiology and Antibiotic Resistance in Enteric Fever: A Comprehensive Review.

Enteric fever, predominantly caused by Salmonella enterica serovar Typhiand Salmonella enterica serovar Paratyphi, remains a significant global health challenge. This comprehensive review examines the evolving epidemiology and antibiotic resistance associated with enteric fever. We provide an overview of the disease's definition and historical context, highlighting the substantial impact of antibiotic resistance on treatment efficacy. The review details the global burden, incidence trends, and risk factors of enteric fever while elucidating the pathogenesis and clinical manifestations of the disease. A critical analysis of antibiotic resistance mechanisms reveals the alarming rise of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains, complicating treatment regimens and underscoring the need for novel therapeutic strategies. Current treatment protocols, the role of empirical therapy, and the rational use of antibiotics are discussed in depth. Additionally, we explore prevention and control strategies, emphasizing the importance of vaccination programs, sanitation improvements, and effective public health interventions. The review concludes with recommendations for future actions, including enhanced surveillance, research and development of new antibiotics, expansion of vaccination efforts, and improved public health infrastructure. The findings highlight the necessity for updated clinical guidelines and sustained global efforts to address the challenges of enteric fever and its evolving antibiotic resistance patterns. Through coordinated action and continued innovation, it is possible to mitigate the impact of this enduring public health threat.

Bioactive Streptomycetes: A Powerful Tool to Synthesize Diverse Nanoparticles With Multifarious Properties.

Nanobiotechnology has gained significant attention due to its capacity to generate substantial benefits through the integration of microbial biotechnology and nanotechnology. Among microbial organisms, Actinomycetes, particularly the prominent genus Streptomycetes, have garnered attention for their prolific production of antibiotics. Streptomyceteshave emerged as pivotal contributors to the discovery of a substantial number of antibiotics and play a dominant role in combating infectious diseases on a global scale. Despite the noteworthy progress achieved through the development and utilization of antibiotics to combat infectious pathogens, the prevalence of infectious diseases remains a prominent cause of mortality worldwide, particularly among the elderly and children. The emergence of antibiotic resistance among pathogens has diminished the efficacy of antibiotics in recent decades. Nevertheless, Streptomycetes continue to demonstrate their potential by producing bioactive metabolites for the synthesis of nanoparticles. Streptomycetes are instrumental in producing nanoparticles with diverse bioactive characteristics, including antiviral, antibacterial, antifungal, antioxidant, and antitumor properties. Biologically synthesized nanoparticles have exhibited a meaningful reduction in the impact of antibiotic resistance, providing resources for the development of new and effective drugs. This review succinctly outlines the significant applications of Streptomycetes as a crucial element in nanoparticle synthesis, showcasing their potential for diverse and enhanced beneficial applications.

Evaluation of Antibacterial Functionalized Dihydropyrimidine Photoaffinity Probes Toward Mechanism of Action Studies.

Antibiotic-resistant bacteria are a global health concern, necessitating the development of antibiotics working through new or underutilized mechanisms. Functionalized amino dihydropyrimidines have previously demonstrated potential as antibacterial agents, but they had limited potency, and their biological mechanism was not understood. To further evaluate their potential, focused libraries were prepared and screened for bacterial growth inhibition, and these compounds provided additional insights into the structure-activity relationships, allowing for the preparation of compounds that inhibited all strains of Staphylococcus aureus with an MIC of 2 μg/mL. After eliminating the proposed mechanism of dihydrofolate reductase inhibition, trifluoromethyl diazirine photoaffinity probes were synthesized to investigate their mechanism, and these were tested to ensure the photolabile group did not impact the antibacterial activity. Finally, the compounds were screened for hemolysis and mammalian cytotoxicity. While they lacked nonspecific membrane rupturing activity, many of the compounds showed significant mammalian cytotoxicity, indicating further development will be required to render them selective for bacteria.

Antibacterial mechanism and structure-activity relationships of Bombyx mori cecropin A.

Bombyx mori cecropin A (Bmcecropin A) has antibacterial, antiviral, anti-filamentous fungal and tumour cell inhibition activities and is considered a potential succedaneum for antibiotics. We clarified the antibacterial mechanism and structure-activity relationships and then directed the structure-activity optimization of Bmcecropin A. Firstly, we found Bmcecropin A shows a strong binding force and permeability to cell membranes like a detergent; Bmcecropin A could competitively bind to the cell membrane with the cell membrane-specific dye DiI, then damaged the membrane for the access of DiI into the cytoplasm and leading to the leakage of electrolyte and proteins. Secondly, we found Bmcopropin A could also bind to and degrade DNA; furthermore, DNA library polymerase chain reaction (PCR) results indicated that Bmcecropin A inhibited DNA replication by non-specific binding. In addition, we have identified C-terminus amidation and serine-lysine- glycine (SLG) amino acids of Bmcecropin A played critical roles in the membrane damage and DNA degradation. Based on the above results, we designed a mutant of Bmcecropin A (E9 to H, D17 to K, K33 to A), which showed higher antibacterial activity, thermostability and pH stability than ampicillin but no haemolytic activity. Finally, we speculated that Bmcecropin A damaged the cell membrane through a carpet model and drew the schematic diagram of its antibacterial mechanism, based on the antibacterial mechanism and the three-dimensional configuration. These findings yield insights into the mechanism of antimicrobial peptide-pathogen interaction and beneficial for the development of new antibiotics.