Antibacterial Spectrum Research Articles

Role of glycosylation in bacterial resistance to carbapenems.

Carbapenems are a class of β-lactam antibacterial drugs with a broad antibacterial spectrum and strong activity, commonly used to treat serious bacterial infections. However, improper or excessive use of carbapenems can lead to increased bacterial resistance, which is a significant concern as they are often used as last resort for treating multidrug-resistant (MDR) gram-negative bacteria. Confronted with this challenge, it is crucial to comprehensively understand the mechanism of carbapenem resistance to develop effective therapeutic strategies and innovative drugs. In recent years, emerging research on the glycosylation of bacterial proteins has highlighted the crucial role of glycans in various bacterial processes, including carbapenem resistance. Given the limited understanding of bacterial glycosylation, its role in in carbapenem resistance may be more pivotal than currently acknowledged. In this review, we summarize the direct and multifunctional role of glycosylation in bacterial resistance as well as the classical and recently reported mechanisms of bacterial carbapenem resistance, focusing on illuminating the potential role of glycosylation in carbapenem resistance. We also discuss the potential of leveraging this knowledge to develop more effective strategies for combating clinically resistant bacteria.

Rational Design of Natural Xanthones Against Gram-negative Bacteria.

Most antibiotics are ineffective against Gram-negative bacteria owing to the existence of the outer membrane (OM) barrier. The rational design of compounds to expand their antibacterial spectra of antibiotics solely targeting Gram-positive pathogens remains challenging. Here, the design of skeletons from natural products to penetrate the OM are deciphered. Structure-activity relationship analysis shows the optimization of the model of natural xanthones α-mangostin endows the broad-spectrum antibacterial activity. Mechanistic studies demonstrate the lead compound A20 penetrates the OM in a self-promoted pathway through electronic and hydrophobic interactions with lipopolysaccharides and phospholipids in OM. A20 displays rapid bactericidal activity by targeting the cofactor heme in the respiratory complex. The therapeutic efficacy of A20 is demonstrated in two animal models infected with multidrug-resistant Gram-negative bacterial pathogens. The findings elucidate the structural property and self-promoted transportation of a class of antibacterial compounds, to facilitate the design and discovery of antibacterial agents against increasingly prevalent Gram-negative pathogens associated with infections.

Genome-Guided Identification and Characterisation of Broad-Spectrum Antimicrobial Compounds of Bacillus velezensis Strain PD9 Isolated from Stingless Bee Propolis.

The emergence of multidrug-resistant pathogens presents a significant global health challenge, which is primarily fuelled by overuse and misuse of antibiotics. Bacteria-derived antimicrobial metabolites offer a promising alternative strategy for combating antimicrobial resistance issues. Bacillus velezensis PD9 (BvPD9), isolated from stingless bee propolis, has been reported to have antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to characterise and identify the antimicrobial compounds (AMCs) synthesised by BvPD9 through integration of genome mining and liquid chromatography-mass spectrometry (LC-MS) analysis. The whole-genome sequence of BvPD9 contained 4,263,351 base pairs and 4101 protein-coding sequences, with 12 potential AMC biosynthetic gene clusters. Comparative genomic analysis highlighted the unique profile of BvPD9 that possesses the largest number of unknown proteins, indicating significant potential for further exploration. The combined genomics-metabolic profiling uncovered five AMCs in BvPD9 extract, including bacillibactin, bacilysin, surfactin A, fengycin A, and bacillomycin D. The extract exhibited a broad antibacterial spectrum against 25 pathogenic bacteria, including both Gram-positive and Gram-negative bacteria, with the lowest minimum inhibitory concentration (MIC, 0.032mg/ml) against S. epidermidis ATCC 12228, and the lowest minimum bactericidal concentration (MBC; 0.128mg/ml) against MRSA ATCC 700699 and Aeromonas hydrophilia. The robust stability of BvPD9 extract was demonstrated at high temperatures, over a wide range of pH conditions (6 to 12) and in the presence of various hydrolytic enzymes. Additionally, the extract showed 50% haemolytic and cytotoxicity activity at 0.158 and 0.250mg/ml, respectively. These characteristics suggest potential applications of BvPD9 metabolites for tackling antimicrobial resistance and its applicability across diverse industries.

Characterization and bioinformatic analysis of a new chimeric endolysin against MRSA with great stability

Antibiotics become less effective in treating infectious diseases as resistance increases. Staphylococcus aureus is a global problem due to its ability to form biofilms and resistance mechanisms. Phage endolysin is one of the most promising methods for combating antibiotic resistance. ZAM-MSC chimeric endolysin has three domains derived from SAL1 and lysostaphin, which target the peptide bridge of peptidoglycan. In this study purified ZAM-MSC (with yield of 30 mg/lit) had bactericidal activity against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) at low concentrations (2.38 μg/ml and 1.88 μg/ml, respectively). The antibacterial spectrum revealed that ZAM-MSC was active against diverse Staphylococci. it has maintained 100% stability after 24 h incubation in pH 5 to 10 against S. aureus, as well as demonstrated significant thermostability and maintained nearly its full activity at different temperatures (4–42 °C) up to 1 day of incubation. The anti-biofilm activity of various concentrations of ZAM-MSC against MSSA and MRSA biofilms was not dose-dependent, and antibiofilm activity was observed even at low concentrations (14 μg/ml). Further, the molecular dynamics simulations demonstrated that the ZAM-MSC chimer and its parent proteins remained dynamically stable, showing similar flexibility despite the size and hydrogen bond number differences. In conclusion, the study reveals that chimeric ZAM-MSC is a distinctive enzyme with exceptional biochemical properties and rapid lytic activity against Staphylococci.

Antibacterial Activity of Indonesian Local Honey Against Strains of P. Aeruginosa, S. Aureus and MRSA

Background: Honey has been used in wound care since ancient times. Many publications attest antibacterial activity of manuka honey against Pseudomonas aeruginosa, S. aureus, and Methicillin-resistant S. aureus (MRSA). However, antibacterial effect of local honey from Indonesia has never been studied and compared to medical grade honey before. This study aim to compare antibacterial activity of local honey and manuka honey against P. aeruginosa, S. aureus and MRSA.Methods: The honeys were tested for their antimicrobial activities with broth dilution method. Different concentrations of honey were prepared in reaction tubes. Strains of P.aeruginosa, S. aureus, and MRSA were grown in nutrient broth. These strains of bacteria then added to the different concentrations of honey. Minimum Inhibitory Concentrations (MIC) is the lowest concentration of the honey that yielded no growth of bacteria.Results: MIC of local honey for P. aeruginosa is 50%, for S. aureus is 100% and for MRSA is 100%. MIC of manuka honey for P. aeruginosa is 12,5%, for S. aureus is 25%, and for MRSA is 12,5%.Conclusion: Nusantara Manuka have the similar antibacterial activity spectrum against P. aeruginosa, MRSA and S. aureus, but it must be given in greater concentration to exert the same level of antibacterial activity with Manuka honey.

Development of Nano-Silver Functionalized Wound Dressings Using Wrightia tinctoria Extract for Enhanced Antibacterial Activity Against MRSA and Staphylococcus aureus

Wound infections remain a major source of postoperative morbidity, accounting for about a quarter of the total number of nosocomial infections. This leads to errors in establishing the true incidence of their occurrence but undoubtedly decreases the overall real cost and length of hospital stay. The healing of defected skin tissue is a complex process, especially for chronic wounds. Poor healing of these wounds may cause extensive suffering and high cost for patients. Traditional wound dressings are typically designed for a single function and they cannot satisfy all requirements for the whole process of wound healing. So it is essential to develop new types of wound dressings with many functions for wound healing. In specific, adding an antibacterial function to the dressings has been shown to be of great benefit during healing of any kind of wounds. Nano‑silver is widely used in wound treatment as of various advantages, it has wide antibacterial spectrum and lower drug resistance. Therefore, wound dressings loaded with nano‑silver have attracted widespread attention in wound healing. In this work we focused on nano‑silver functionalized wound dressings including their preparation methods, antibacterial performances and classification of nano‑silver wound dressings. The toxicity of nano‑silver based wound dressings is discussed and the prospective research direction is elaborated. This work aims to provide a little guidance for the research of nano‑silver functionalized polysaccharide-based wound dressings. The study showed the ability to synthesize environmentally friendly silver nanoparticles (AgNPs) using extracts from Wrightia tinctoria.

Bacteriocin CM175, a new high molecular weight and phage associated protein produced by Pediococcus pentosaceus CM175

Bacteriocins are proteins with antimicrobial capacity produced by different bacteria. Developing bacteriocin-based technologies could be an effective strategy to address current problems in the pharmaceutical and food industries, including limited therapeutic options against superbug infections, foodborne diseases, and food spoilage microorganisms. The lactic acid bacteria Pediococcus pentosaceus are known producers of bacteriocins. Particularly, Ped. pentosaceus strain CM175 has been reported to produce an uncharacterized bacteriocin-like inhibitory substance (BLIS) with an interesting antibacterial spectrum against Gram-positive and -negative pathogenic bacteria. The objective of the present study was to explore whether the BLIS produced by CM175 contains at least one bacteriocin, and identify it. Our results showed that the CM175 strain produced a non-previously characterized antimicrobial protein of 49 kDa identified by mass spectrometry as a phage-related protein, named bacteriocin CM175. Through fluorescence and transmission electron microscopies, it was demonstrated that bacteriocin CM175 damages the cell membrane integrity of Listeria monocytogenes through a non-lytic mechanism. Bacteriocin CM175 is the first high molecular weight and phage protein-like bacteriocin reported in Ped. pentosaceus. The results of this study open the possibility of exploring various applications directly related to the antimicrobial potential of bacteriocin CM175, including the development of antibiotics, and disinfectants.

Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research.

In the fight against bacterial infections, particularly those caused by multi-resistant pathogens, the need for new antibacterials is undoubted in scientific communities. and is by now also widely perceived by the general population. However, the antibacterial research landscape has changed considerably over the past years. The majority of big pharma companies has left the field and thus, the decline in R&D on antibacterials severely impacts the drug pipeline. In past years, antibacterial research increasingly relies on smaller companies or academic research institutions, which mostly have only limited financial resources, to carry a drug discovery and development process from the beginning and through the clinical phases. This review formulates the requirements for an antibacterial in regard of targeted pathogens and resistance mechanisms. Strategies are shown for the discovery of new antibacterial structures originating from natural sources, chemical synthesis and more recent AI approaches. This is complemented by principles for the computer-aided design of antibacterials and the refinement of a lead structure. The second part of the article comprises a compilation of promising antibacterial molecules classified according to bacterial target areas. Aspects of the origin, the antibacterial spectrum, resistance and the current development status of the presented drug molecules are highlighted.

Scaling up production of cephalosporin C by Acremonium chrysogenum W42-I in a fermenter using submerged fermentation.

Cephalosporins presently stand as the most extensively utilized antibiotic in clinical settings. Acremonium (A.) chrysogenum is the main strain used in the manufacturing of cephalosporin C (CPC), which offers distinct advantages, including a wide-ranging antibacterial spectrum and powerful antibacterial efficacy. Our study aimed to determine the optimal conditions for scaling up the production of CPC from A. chrysogenum W42-I starting with the optimized conditions on the shake flask level obtained from our previous study and utilizing the optimized media (CPC2). The results indicated that an inoculum size equivalent to 1% v/v, aeration at 1 vvm, and an agitation rate of 400rpm, with controlled pH at 4, were the most favorable conditions for the CPC production using a laboratory fermentor (14L). The concentration of generated CPC was assessed using two standard curves obtained from agar well diffusion and high-performance liquid chromatography (HPLC). These optimized conditions resulted in a production of 399.52µg/mL showing a significant increase of approximately 3.4 folds when compared to the unoptimized fermentation run. In conclusion, our findings demonstrated a more favorable time course for CPC production in the fermentor compared to that in the shake flask. Notably, there was a two-fold increase in production within the first three days. Fortunately, the fermentor achieved a noteworthy increase in output, generating 1.598 gm of the CPC within 4L.

Unraveling Neurotoxicity Discrepancies: Comparative In vitro and In vivo Analysis of Colistin and Polymyxin B and the Underlying Mechanisms.

Polymyxins, including colistin and polymyxin B, are the final resort against Gram-negative bacterial infections. However, its clinical application is restricted due to concerns related to neurotoxicity. Despite the similar antibacterial spectrum and mode of action shared between colistin and polymyxin B, there is still a lack of definitive evidence to support the idea that their neurotoxicity profiles are identical. To comprehensively compare the neurotoxicity between colistin and polymyxin B both in vivo and in vitro and establish a theoretical foundation to guide the rational use of polymyxins within clinical settings. in vitro experiments simulated nerve damage by exposing N2a and RSC96 cells to colistin and polymyxin B. The evaluation of nerve injury included assessments of cell viability and apoptosis. To discern the variance in the mechanisms of nerve injury between colistin and polymyxin B, oxidative stress levels were examined, such as SOD, CAT, GSH, and malondialdehyde (MDA). In in vivo experiments, a rat nerve injury model was created by intraventricular injections of colistin and polymyxin B, respectively. The impact of these drugs on brain injury in rats, particularly within the hippocampus and medulla oblongata, was measured using HE and Nissl staining. The potential influence of polymyxins on the ferroptosis pathway was evaluated by assessing LPO and Fe2+ levels and the degree of mitochondrial impairment. At equivalent doses, colistin demonstrated a reduced level of neurotoxicity compared to polymyxin B, both in vitro and in vivo. in vitro experiments revealed greater cell viability and a lower apoptosis rate after colistin treatment than after polymyxin B treatment. This variance in outcomes could be attributed to the comparatively lower levels of oxidative stress associated with colistin administration.In a rat model, nerve injury resulted in observable damage to both the hippocampus and the medulla oblongata. A comprehensive assessment of the extent of damage in the CA1 to CA4 regions of the hippocampus, and the solitary tract nucleus of the medulla oblongata underscored that the neurotoxic effects of colistin remained milder compared to those elicited by polymyxin B. Even when evaluated at equivalent multiples of clinically recommended doses, colistin exhibited lower neurotoxicity in vivo than polymyxin B. For the first time, this study demonstrated the role of ferroptosis in polymyxin B-induced nerve damage. The activation levels observed within the ferroptosis pathway due to polymyxin B exceeded those triggered by colistin. Colistin exhibited a marked reduction in neurotoxicity compared to polymyxin B, evident in both the equivalent and clinically recommended doses. These findings suggest that, from the perspective of neurotoxicity, colistin presents a more favorable option for clinical use.

Antimicrobial Potential of Scorpion-Venom-Derived Peptides.

The frequent and irrational use of antibiotics by humans has led to the escalating rise of antimicrobial resistance (AMR) with a high rate of morbidity-mortality worldwide, which poses a challenge to the development of effective treatments. A large number of host defense peptides from different organisms have gained interest due to their broad antibacterial spectrum, rapid action, and low target resistance, implying that these natural sources might be a new alternative to antimicrobial drugs. As important effectors of prey capture, defense against other animal attacks, and competitor deterrence, scorpion venoms have been developed as important candidate sources for modern drug development. With the rapid progress of bioanalytical and high throughput sequencing techniques, more and more scorpion-venom-derived peptides, including disulfide-bridged peptides (DBPs) and non-disulfide-bridged peptides (NDBPs), have been recently identified as having massive pharmacological activities in channelopathies, pathogen infections, and cancer treatments. In this review, we summarize the molecular diversity and corresponding structural classification of scorpion venom peptides with antibacterial, antifungal, and/or antiparasitic activity. We also aim to improve the understanding of the underlying mechanisms by which scorpion-venom-derived peptides exert these antimicrobial functions, and finally highlight their key aspects and prospects for antimicrobial therapeutic or pharmaceutical application.

Antimicrobial Activity of Commercial Essential Oils Available in the Market of Kathmandu

Given the increasing global apprehension surrounding antibiotic resistance, there has been growing interest in exploring natural compounds, specifically essential oils, as potential substitutes for combating microbial pathogens. This research work aimed to evaluate the antimicrobial activity exhibited by commercial essential oils and by diluting them with the carrier oils at equal concentration. The screening of antimicrobial activity was conducted using the agar well diffusion method with eight essential oils. Using the broth dilution method, the antibacterial activity of eight commonly used essential oils: lavender, tea tree, eucalyptus, peppermint, thyme, citrus, rosemary, and cinnamon were assessed. Both Gram-positive and Gram-negative species were selected for antimicrobial activity. The minimum inhibitory concentration (MIC) was determined by the broth dilution method. Following MIC determination, a sub-culture was performed on nutrient agar plates to ascertain the minimum bactericidal concentration (MBC). All the antibiotics used in the study demonstrated sensitivity when subjected to the antibiotic susceptibility test. Thyme, cinnamon and peppermint strongly inhibited the growth of S. epidermidis 46 mm, 30mm, and 34 mm respectively. Findings revealed distinct variations in the MIC values among the different essential oils and bacteria tested. Thyme and tea tree oils exhibited the broadest antibacterial spectrum, inhibiting both Gram-positive and Gram-negative bacteria at relatively low concentrations. Thyme (15.625 μl/ml) and tea tree (31.25 μl/ml) oil demonstrated promising activity against Gram-positive pathogen, while tea tree oil (15.625 μl/ml) displayed better efficacy against Gram-negative bacteria. A significant outcome was observed when the essential oils were diluted with carrier oils, indicating promising results in terms of antibacterial activity. These findings highlight the potential of essential oils, particularly thyme and tea tree oils, as effective natural antimicrobial agents.

Campycins are novel broad-spectrum antibacterials killing Campylobacter jejuni

Pyocins are high molecular weight bacteriocins produced by Pseudomonas aeruginosa that can be retargeted to new bacterial species by exchanging the pyocin tail fibers with bacteriophage receptor binding proteins (RBPs). Here, we develop retargeted pyocins called campycins as new antibacterials to precisely and effectively kill the major foodborne pathogen Campylobacter jejuni. We used two diverse RBPs (H-fibers) encoded by CJIE1 prophages found in the genomes of C. jejuni strains CAMSA2147 and RM1221 to construct campycin 1 and campycin 2, respectively. Campycins 1 and 2 could target all C. jejuni strains tested due to complementary antibacterial spectra. In addition, both campycins led to more than 3 log reductions in C. jejuni counts under microaerobic conditions at 42 °C, whereas the killing efficiency was less efficient under anaerobic conditions at 5 °C. Furthermore, we discovered that both H-fibers used to construct the campycins bind to the essential major outer membrane protein (MOMP) present in all C. jejuni in a strain-specific manner. Protein sequence alignment and structural modeling suggest that the highly variable extracellular loops of MOMP form the binding sites of the diverse H-fibers. Further in silico analyses of 5000 MOMP sequences indicated that the protein falls into three major clades predicted to be targeted by either campycin 1 or campycin 2. Thus, campycins are promising antibacterials against C. jejuni and are expected to broadly target numerous strains of this human pathogen in nature and agriculture.Key points• Campycins are engineered R-type pyocins containing H-fibers from C. jejuni prophages• Campycins reduce C. jejuni counts by >3 logs at conditions promoting growth• Campycins bind to the essential outer membrane protein MOMP in a strain-dependent way

Evaluation of Antibacterial and Antibiofilm Effects from Soil Streptomyces spp. against Multidrug-Resistant Bacteria

The global increase in multidrug-resistant (MDR) bacterial infection has rapidly gained concern globally. This study aimed to investigate antibacterial and antibiofilm potential of 25 soil actinomycete strains against MDR strains including Escherichia coli strain M4, Pseudomonas aeruginosa strain M19, Klebsiella pneumoniae strain M19, Bacillus subtilis strain M18, and Methicillin Resistant Staphylococcus aureus (MRSA). In this study, three actinomycete isolates encoded APM-7, APM-11, and APM-21 showed a strong and broad antibacterial spectrum. The minimum inhibitory concentration (MIC) of extracts derived from these isolates was ranged from 78 μg/ml to 10,000 μg/ml. In addition, The extracts also displayed significant biofilm inhibition values ranging from 6.06 to 72.4%. Based on the results, APM-21 extract had the best antibacterial and antibiofilm activities with the strongest values against MRSA. According to the nucleotide sequencing of the 16S rRNA gene, APM-7, APM-11, and APM-21 strains possessed similar identities with Streptomyces cyaneus, Streptomyces coerulescens, and Streptomyces panayensis, respectively. Based on Liquid Chromatography Tandem-Mass Spectrometry (LC-MS/MS) analysis, two antibacterial compounds, namely rancimanycin III, and enteromycin were detected in all those three extracts. Interestingly, APM-21 extract also contained two prominent antibacterial substances including paramagnetoquinone C, and caerulomycin I, suggesting their contribution to the most potential activities. Moreover, new insights were provided into a promising candidate for use in an active compound combating strategy to control MDR bacterial strain infection.

Characterization of Two Novel Endolysins from Bacteriophage PEF1 and Evaluation of Their Combined Effects on the Control of Enterococcus faecalis Planktonic and Biofilm Cells.

Endolysin, a bacteriophage-derived lytic enzyme, has emerged as a promising alternative antimicrobial agent against rising multidrug-resistant bacterial infections. Two novel endolysins LysPEF1-1 and LysPEF1-2 derived from Enterococcus phage PEF1 were cloned and overexpressed in Escherichia coli to test their antimicrobial efficacy against multidrug-resistant E. faecalis strains and their biofilms. LysPEF1-1 comprises an enzymatically active domain and a cell-wall-binding domain originating from the NLPC-P60 and SH3 superfamilies, while LysPEF1-2 contains a putative peptidoglycan recognition domain that belongs to the PGRP superfamily. LysPEF1-1 was active against 89.86% (62/69) of Enterococcus spp. tested, displaying a wider antibacterial spectrum than phage PEF1. Moreover, two endolysins demonstrated lytic activity against additional gram-positive and gram-negative species pretreated with chloroform. LysPEF1-1 showed higher activity against multidrug-resistant E. faecalis strain E5 than LysPEF1-2. The combination of two endolysins effectively reduced planktonic cells of E5 in broth and was more efficient at inhibiting biofilm formation and removing biofilm cells of E. faecalis JCM 7783T than used individually. Especially at 4 °C, they reduced viable biofilm cells by 4.5 log after 2 h of treatment on glass slide surfaces. The results suggest that two novel endolysins could be alternative antimicrobial agents for controlling E. faecalis infections.

An insight into the applications of bacteriophages against food-borne pathogens.

Novel and emerging pathogens, enduring contamination, antibiotic resistance, an environment that is always changing, and the complexity of food production systems all contribute to the worsening of foodborne illness. It has been proposed that bacteriophages can serve as both fast food-borne pathogen detection tools and natural food preservatives in a variety of foods. Phages, like many other antimicrobial interventions used in food production systems, are not a cure-all for issues related to food safety, though. Consequently, phage-based biocontrol has a generally narrower antibacterial spectrum than most antibiotics, even though it can be promising in the fight against foodborne infections. Among the difficulties phage-based biocontrol techniques encounter are forming phage-insensitive single-cell variations and creating potent cocktails. To better understand when and where phage-based applications can be successfully implemented at the production and processing levels, this review focuses on phage-based applications at crucial control points in food production systems.

Cefotaxime Versus Ceftriaxone: A Comprehensive Comparative Review.

Cefotaxime and ceftriaxone are two prominent third-generation cephalosporin antibiotics, which are a class of antimicrobial agents with overlapping antibacterial spectra and therapeutic indications, commonly used in treating severe bacterial infections, including meningitis, sepsis, and respiratory tract infections. Despite their shared antibacterial coverage, these antibiotics differ significantly in their pharmacokinetic characteristics such as half-life, protein binding, and tissue penetration. This comprehensive review systematically compares the pharmacokinetic profiles, pharmacological attributes, clinical efficacy, and safety profiles of cefotaxime and ceftriaxone. It further highlights the importance of understanding the nuanced differences between cefotaxime and ceftriaxone, particularly in clinical settings such as intensive care units or during pediatric treatment, where rapid bactericidal action or prolonged drug activity might influence therapeutic outcomes. While their overlapping spectrums offer versatility, clinicians should consider these distinct pharmacokinetic attributes and associated clinical outcomes to guide optimal antibiotic selection.

Design and synthesis of Thieno[3, 2-b]pyridinone derivatives exhibiting potent activities against Mycobacterium tuberculosis in vivo by targeting Enoyl-ACP reductase

In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5–1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents.

Isolation, Identification and Antibacterial Characteristics of Lacticaseibacillus rhamnosus YT.

Pathogenic microorganisms have been detected in fermented food. Combining the enormous class of the pathogens and their continuously appearing mutants or novel species, it is important to select suitable and safe antibacterial agents for fermented food safety. Lactic acid bacteria (LAB) which produce diverse imperative antimicrobial metabolites have an immense number of applications in the food industry. Here, the human-derived strain YT was isolated due to its cell-free supernatant (CFS-YT) and cells (Cs-YT), respectively performed obvious inhibitory ring to Gram-positive and -negative spoilage bacteria. Strain YT was identified as Lacticaseibacillus rhamnosus by the 16s rDNA sequence and morphology. The antibacterial activity of CFS-YT was demonstrated to be growth-dependent, pHs-sensitive, broadly thermostable and enzyme-insensitive. Cs-YT displayed a broad antibacterial spectrum with the action mode of bacteriostasis. The antibacterial activity of Cs-YT was due to substances located at the cell surface which were sensitive to heat, stable at broad pH gradients and sensitive to specific enzymes. These data suggested that L. rhamnosus YT could be used as an alternative antimicrobial agent in fermented food biopreservation.

Mechanistic Basis for the Translation Inhibition of Cutibacterium acnes by Clindamycin

Inflammation and the Gram-positive anaerobic bacterium Cutibacterium acnes, which is implicated in acne pathogenesis and pilosebaceous unit inflammation, are the main targets of antibiotic-based therapy against acne vulgaris (acne). The most widely used antibiotics in acne therapy are tetracyclines, macrolides, and lincosamides. Unfortunately, C. acnes bacteria over the past several decades have demonstrated increased resistance to these antibiotics, particularly to clindamycin. The precise knowledge of how antibiotics interact with their clinical target is needed to overcome this problem. Toward this goal, we determined the structure of clindamycin in complex with the ribosome of Cutibacterium acnes at 2.53 Å resolution using cryogenic electron microscopy. The galactose sugar moiety of clindamycin interacts with nucleotides of the 23S rRNA directly or through a conserved network of water-mediated interactions. Its propyl pyrrolidinyl group interacts with the 23S rRNA through van der Waals forces. Clindamycin binding to the Cutibacterium acnes ribosome interferes with both: proper orientation of the aminoacyl group of the A-site bound tRNA that is needed for peptide bond formation and with the extension of the nascent peptide. Our data are important for advancing understanding of antibiotic resistance and development of narrow- spectrum antibacterial drugs, which is an urgent need for contemporary antibiotic stewardship.