Development Of New Antibacterial Drugs Research Articles

Synthesis and anti-bacterial activity of barbituric acid derivatives

When the viable solve the ents businesses launched penicillin, in the establishment of 19th century vented by Alexander Fleming, a major reduction in the number of deaths caused by bacterial infections was confirmed. Optimists have even noticed an end to the period of bacterial diseases. However, to the request, and frequently improper, applications of antibiotics have resulted in the development of drug-the resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), WHO generated a list of priority pathogens to focus the development of new antibacterial drugs against; MRSA ranked as a high priority. Unfortunately, the development of new antibacterial drugs has progressively declined since the 1980s. In my the research work novel derivatives of Barbituric acid obtained from Methyl propyl malonate and Thiourea give 5-methyl-5-propyl-2-sulfanyl Barbituric Acid [ST-I] it was treated with Alkyl Halides gives 5-methyl-5-propyl-2-sulfanyl Barbituric Acid Derivatives which is converted into resultant compound derivatives of (ST-IA to ST-IE). All the compounds synthesized were confirmed by spectral data and evaluated for their methicillin-resistant Staphylococcus aureus (MRSA) activity Vancomycin was used as standard. The compounds DR-IIA and DR-IID have shown good activity and the remaining show poor activity against bacteria.

Molecular mechanism of action of imidazolium carbosilane dendrimers on the outer bacterial membrane – From membrane damage to permeability to antimicrobial endolysin

The outer bacterial membrane of drug-resistant bacteria is a significant barrier to many antimicrobials. Therefore, the development of new antibacterials primarily focuses on damaging the outer bacterial membrane of Gram-negative bacteria. Among many membrane-disrupting substances, the most promising are cationic dendritic systems. However, the mode of action may vary among different strains due to variations in the lipid compositions of the membrane. Here, we investigated the interaction of two types of cationic imidazolium carbosilane dendrimers: one with a single cationic group (methyl imidazolium) and the other with the same cationic group but attached to a functional group (a pendant pyridyl moiety), capable of establishing interactions with membranes through H-bonding or ion–dipole electrostatic interactions. We used different models of the outer membrane of Gram-negative bacteria – Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. Additionally, we assessed the combined effect of the dendrimers and the antibacterial endolysin on P. aeruginosa. Our results show that the mechanism of action depends on the type of dendrimer and the lipid composition of the membrane. We also demonstrate that the alteration of membrane fluidity and permeability to endolysin by the methyl imidazolium and pyridyl imidazolium dendrimers may play a more significant role in antimicrobial activity compared to membrane damage caused by positively charged dendrimers.

Tetramerization is essential for the enzymatic function of the Pseudomonas aeruginosa virulence factor UDP-glucose pyrophosphorylase.

Multidrug-resistant bacteria such as the opportunistic pathogen Pseudomonas aeruginosa, which causes life-threatening infections especially in immunocompromised individuals and cystic fibrosis patients, pose an increasing threat to public health. In the search for new treatment options, P. aeruginosa uridine diphosphate-glucose pyrophosphorylase (PaUGP) has been proposed as a novel drug target because it is required for the biosynthesis of important virulence factors and linked to pathogenicity in animal models. Here, we show that UGP-deficient P. aeruginosa exhibits severely reduced virulence against human lung tissue and cells, emphasizing the enzyme's suitability as a drug target. To establish a basis for the development of selective PaUGP inhibitors, we solved the product-bound crystal structure of tetrameric PaUGP and conducted a comprehensive structure-function analysis, identifying key residues at two different molecular interfaces that are essential for tetramer integrity and catalytic activity and demonstrating that tetramerization is pivotal for PaUGP function. Importantly, we show that part of the PaUGP oligomerization interface is uniquely conserved across bacterial UGPs but does not exist in the human enzyme, therefore representing an allosteric site that may be targeted to selectively inhibit bacterial UGPs.IMPORTANCEInfections with the opportunistic bacterial pathogen Pseudomonas aeruginosa are becoming increasingly difficult to treat due to multidrug resistance. Here, we show that the enzyme uridine diphosphate-glucose pyrophosphorylase (UGP) is involved in P. aeruginosa virulence toward human lung tissue and cells, making it a potential target for the development of new antibacterial drugs. Our exploration of P. aeruginosa (Pa)UGP structure-function relationships reveals that the activity of PaUGP depends on the formation of a tetrameric enzyme complex. We found that a molecular interface involved in tetramer formation is conserved in all bacterial UGPs but not in the human enzyme, and therefore hypothesize that it provides an ideal point of attack to selectively inhibit bacterial UGPs and exploit them as drug targets.

Lactobacilli and Klebsiella: Two Opposites in the Fight for Human Health.

The problem of antibiotic resistance is currently very acute. Numerous research and development of new antibacterial drugs are being carried out that could help cope with various infectious agents. One of the promising directions for the search for new antibacterial drugs is the search among the probiotic strains present in the human gastrointestinal tract. This review is devoted to characteristics of one of these probiotic strains that have been studied to date: Limosilactobacillus reuteri. The review discusses its properties, synthesis of various compounds, as well as role of this strain in modulating various systems of the human body. The review also examines key characteristics of one of the most harmful among the currently known pathogenic organisms, Klebsiella, which is significantly resistant to antibiotics existing in medical practice, and also poses a great threat of nosocomial infections. Discussion of characteristics of the two strains, which have opposite effects on human health, may help in creation of new effective antibacterial drugs without significant side effects.

Rhenium (I) tricarbonyl complex with thiosemicarbazone ligand derived from Indole-2-carboxaldehyde: Synthesis, crystal structure, computational investigations, antimicrobial activity, and molecular docking studies

Antibiotic resistance is becoming a cause of serious concern to human health causing a significant impact on the global economy. The demand for novel antimicrobial agents is pressing since drug resistance is spreading and making antibiotics less and less effective. There is unrealized antibacterial potential in metal complexes. Among other compounds, rhenium complexes are particularly appealing because of their strong antibacterial activity and minimal in vivo toxicity. In this study, three Re carbonyl thiosemicarbazone (TSC) complexes were synthesized and characterized and their antibacterial potential was evaluated against various types of gram-positive and gram-negative bacteria. The structure of the ligands and their corresponding Re complexes were optimized at the DFT/B3LYP level of theory employing 6–311++G(d,p) and LANL2DZ basis sets for C, H, N, O, S, and Re atoms respectively. The MS studies performed with time show that [fac-[Re(CO)3Br(HL)] was converted into dimer [Re2(CO)6(L)2] in solution and the crystal structure of the dimer [Re2(CO)6(L)2] obtained as the result of dimerization of the complex was solved. Among the three Re TSC complexes, [fac-[Re(CO)3Br(HL1)] exhibits the greatest antibacterial activity against S.aureus with MIC value 0.5 µg/mL. The data obtained showed that the synthesized complexes were ineffective against gram-negative bacteria but showed excellent antibacterial activity against gram-positive S.aureus. The [fac-[Re(CO)3Br(HL2)] complex derived from isatin-β-thiosemicarbazone showed lesser activity than the other two rhenium TSC complexes which were obtained by condensation of indole-2-carboxaldehyde and thiosemicarbazide. Furthermore, the in-silico molecular docking studies revealed that the binding energy of the docked compound [Re(CO)3Br(HL)] with E. Coli and MRSA targets were extremely favorable (-7.18 and -5.67 kcal/mol, respectively which further demonstrates the potential of the synthesized complexes in the development of new antibacterial drugs. The molecular docking studies as well as experimental investigations demonstrate the effect of substituents on the ligand backbone on the antimicrobial activity of the synthesized rhenium carbonyl complexes. The enhanced antibacterial properties of rhenium carbonyl complexes with the TSC ligands in comparison to the ligand alone also suggest a possible synergistic effect of the metal center and the organic ligand.

Development and validation of a rabbit model of Pseudomonas aeruginosa non-ventilated pneumonia for preclinical drug development.

New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections. We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression. In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5h post-infection, 67% of Pa6206-challenged rabbits had PaO2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits (P<0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24h achieved Cmax/MIC of 9.8 ± 1.4 at 60min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects. The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia.

Progress on mechanisms of antibiotic resistance in Clostridioides difficile.

Clostridioides difficile (CD) is one of the most common pathogens causing health-care-associated infectious diarrhea and is listed by the U.S. Centers for Disease Control and Prevention as an urgent antibiotic resistance (AR) threat. Many resistance genes can be transferred between different CD strains present in the clinical setting, community, and environment. The antimicrobial resistance (AMR) of CD continues to evolve with the emergence and acquisition of new drug resistance mechanisms. CD has developed diverse drug resistance mechanisms, such as drug alteration, modification of the target site, and extrusion of drugs via efflux pumps. Researches have provided comprehensive knowledge about resistance mechanisms of macrolides and quinolones in CD. However, the mechanisms of resistance for metronidazole, vancomycin, and other therapeutic antibiotics against Clostridioides difficile infection (CDI) are only beginning to be elucidated. Some previously unfound mechanisms, such as plasmid-mediated drug resistance in CD, may also play an important role. In this review, we summarize the research progress on drug resistance mechanisms of CD with antimicrobial drugs already used clinically, such as metronidazole, vancomycin, and fidaxomicin, thereby providing the references for the clinical treatment and prevention of CDI, as well as the development of new antibacterial drugs and detection kits for drug resistant bacteria.

Antibacterial activity and action mechanism of curcusionol from Carex siderosticta Hance against Ralstonia nicotianae.

Tobacco bacterial wilt is a typical soil-borne disease caused by Ralstonia nicotianae, which causes huge losses in tobacco production every year. The crude extract of Carex siderosticta Hance was shown to have antibacterial activity against R. nicotianae during our search, and the natural antibacterial components were sought after using bioassay-guided fractionation of the compounds. Ethanol extract of Carex siderosticta Hance with the minimum inhibitory concentration (MIC) value of 100 μg/mL against R. nicotianae in vitro. The potential of these compounds as antibactericides against R. nicotianae were assessed. Curcusionol (1), showed the highest antibacterial activity against R. nicotianae with MIC value of 12.5 μg/mL in vitro. In the protective effect tests, the control effect of curcusionol (1) was 92.31 and 72.60%, respectively, after application of 7 and 14 days, at a concentration of 1500 μg/mL, being comparable to that of streptomycin sulfate at a concentration of 500 μg/mL, confirming that curcusionol (1) showed the potential for the development of new antibacterial drugs. RNA-sequencing, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis confirmed that curcusionol mainly destroys R. nicotianae cell membrane structure and affects quorum sensing (QS) to inhibit pathogenic bacteria. This study revealed that the antibacterial activity of Carex siderosticta Hance makes it a botanical bactericide against R. nicotianae, while curcusionol as lead structures for antibacterial development is obvious by its potent antibacterial activity. © 2023 Society of Chemical Industry.

Structural characterization of a galectin from the marine sponge Aplysina lactuca (ALL) with synergistic effects when associated with antibiotics against bacteria

Lectins presents the ability to interact with glycans and trigger varied responses, including the inhibition of the development of various pathogens. Structural studies of these proteins are essential to better understand their functions. In marine sponges, so far only a few lectins have their primary structures completely determined. Thus, the objective of this work was to structurally characterize and evaluate antibacterial potential, in association with different antibiotics, of the lectin isolated from the marine sponge Aplysina lactuta (ALL). ALL is a homotetramer of 60 kDa formed by four 15 kDa-subunits. The lectin showed affinity only for the glycoproteins fetuin, asialofetuin, mucin type III, and bovine submaxillary mucin type I. The complete amino acid sequences of two isoforms of ALL, named ALL-a and ALL-b, were determined by a combination of Edman degradation and overlapped peptides sequenced by tandem mass spectrometry. ALL-a and ALL-b have 144 amino acids with molecular masses of 15,736 Da and 15,985 Da, respectively. Both structures contain conserved residues typical of the galectin family. ALL is a protein with antibacterial potential, when in association with ampicillin and oxacillin the lectin potentiates its antibiotic effect, included Methicillin-resistant Staphylococcus strains. Thus, ALL shows to be a molecule with potential for the development of new antibacterial drugs.

Residue Lys219 of CpxR is critical in the regulation of the antibiotic resistance of Escherichia coli.

CpxR is a critical regulator in bacterial adaptation to various harmful stresses, and is known to regulate bacterial resistance to commonly used antibiotics, such as aminoglycosides, β-lactams and polypeptides. However, the detailed study of functional residues of CpxR remains insufficient. To investigate the contribution of Lys219 to CpxR's function in regulating antibiotic resistance of Escherichia coli. We performed sequence alignment and conservative analysis of the CpxR protein and constructed mutant strains. We then performed electrophoretic mobility shift assay, real-time quantitative PCR assay, determination of reactive oxygen species (ROS) levels, molecular dynamics simulation, conformational analysis and circular dichroism. All mutant proteins (K219Q, K219A and K219R) lost the cpxP DNA-binding ability. Additionally, the three complemented strains eK219A, eK219Q, and eK219R exhibited lower resistance to copper toxicity and alkaline pH toxicity than eWT. Molecular dynamics analysis revealed that mutation of Lys219 leads to looser and more unstable conformation of CpxR, leading to its decreased binding affinity with downstream genes. Moreover, the Lys219 mutation resulted in the down-regulation of efflux pump genes (acrD, tolC, mdtB and mdtA), leading to the accumulation of antibiotics inside the cells and an increase in ROS production, which significantly reduces antibiotic resistance. The mutation of the key residue Lys219 causes a conformational change that results in the loss of regulatory ability of CpxR, which may potentially reduce to antibiotic resistance. Therefore, this study suggests that targeting the highly conserved sequence of CpxR could be a promising strategy for the development of new antibacterial drugs.

Structural Requirements for Ga3+ Coordination in Synthetic Analogues of the Siderophore Piscibactin Deduced by Chemical Synthesis and Density Functional Theory Calculations.

Stereoselective total synthesis of several analogues of piscibactin (Pcb), the siderophore produced by different pathogenic Gram-negative bacteria, was performed. The acid-sensitive α-methylthiazoline moiety was replaced by a more stable thiazole ring, differing in the configuration of the OH group at the C-13 position. The ability of these Pcb analogues to form complexes with Ga3+ as a mimic of Fe3+ showed that the configuration of the hydroxyl group at C-13 as 13S is crucial for the chelation of Ga3+ to preserve the metal coordination, while the presence of a thiazole ring instead of the α-methylthiazoline moiety does not affect such coordination. A complete 1H and 13C NMR chemical shift assignment of the diastereoisomer mixtures around C9/C10 was done for diagnostic stereochemical disposition. Additionally, density functional theory calculations were performed not only for confirming the stereochemistry of the Ga3+ complex among the six possible diastereoisomers but also for deducing the ability of these to form octahedral coordination spheres with gallium. Finally, the lack of antimicrobial activity of Pcb and Pcb thiazole analogue Ga3+ complexes against Vibrio anguillarum agrees with one of the roles of siderophores in protecting pathogens from metal ion toxicity. The efficient metal coordination shown by this scaffold suggests its possible use as a starting point for the design of new chelating agents or vectors for the development of new antibacterials that exploit the "Trojan horse" strategy using the microbial iron uptake mechanisms. The results obtained will be of great help in the development of biotechnological applications for these types of compounds.

β-Barrel Assembly Machinery (BAM) Complex as Novel Antibacterial Drug Target.

The outer membrane of Gram-negative bacteria is closely related to the pathogenicity and drug resistance of bacteria. Outer membrane proteins (OMPs) are a class of proteins with important biological functions on the outer membrane. The β-barrel assembly machinery (BAM) complex plays a key role in OMP biogenesis, which ensures that the OMP is inserted into the outer membrane in a correct folding manner and performs nutrient uptake, antibiotic resistance, cell adhesion, cell signaling, and maintenance of membrane stability and other functions. The BAM complex is highly conserved among Gram-negative bacteria. The abnormality of the BAM complex will lead to the obstruction of OMP folding, affect the function of the outer membrane, and eventually lead to bacterial death. In view of the important role of the BAM complex in OMP biogenesis, the BAM complex has become an attractive target for the development of new antibacterial drugs against Gram-negative bacteria. Here, we summarize the structure and function of the BAM complex and review the latest research progress of antibacterial drugs targeting BAM in order to provide a new perspective for the development of antibiotics.

Antibiofilm Effect of Biogenic Silver Nanoparticles Combined with Oregano Derivatives against Carbapenem-Resistant Klebsiella pneumoniae.

Resistant bacteria may kill more people than COVID-19, so the development of new antibacterials is essential, especially against microbial biofilms that are reservoirs of resistant cells. Silver nanoparticles (bioAgNP), biogenically synthesized using Fusarium oxysporum, combined with oregano derivatives, present a strategic antibacterial mechanism and prevent the emergence of resistance against planktonic microorganisms. Antibiofilm activity of four binary combinations was tested against enteroaggregative Escherichia coli (EAEC) and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC): oregano essential oil (OEO) plus bioAgNP, carvacrol (Car) plus bioAgNP, thymol (Thy) plus bioAgNP, and Car plus Thy. The antibiofilm effect was accessed using crystal violet, MTT, scanning electron microscopy, and Chromobacterium violaceum anti-quorum-sensing assays. All binary combinations acted against preformed biofilm and prevented its formation; they showed improved antibiofilm activity compared to antimicrobials individually by reducing sessile minimal inhibitory concentration up to 87.5% or further decreasing biofilm metabolic activity and total biomass. Thy plus bioAgNP extensively inhibited the growth of biofilm in polystyrene and glass surfaces, disrupted three-dimensional biofilm structure, and quorum-sensing inhibition may be involved in its antibiofilm activity. For the first time, it is shown that bioAgNP combined with oregano has antibiofilm effect against bacteria for which antimicrobials are urgently needed, such as KPC.

Antibacterial Properties and Computational Insights of Potent Novel Linezolid-Based Oxazolidinones.

The mounting evidence of bacterial resistance against commonly prescribed antibiotics warrants the development of new antibacterial drugs on an urgent basis. Linezolid, an oxazolidinone antibiotic, is a lead molecule in designing new oxazolidinones as antibacterial agents. In this study, we report the antibacterial potential of the novel oxazolidinone-sulphonamide/amide conjugates that were recently reported by our research group. The antibacterial assays showed that, from the series, oxazolidinones 2 and 3a exhibited excellent potency (MIC of 1.17 μg/mL) against B. subtilis and P. aeruginosa strains, along with good antibiofilm activity. Docking studies revealed higher binding affinities of oxazolidinones 2 and 3a compared to linezolid, which were further validated by molecular dynamics simulations. In addition to this, other computational studies, one-descriptor (log P) analysis, ADME-T and drug likeness studies demonstrated the potential of these novel linezolid-based oxazolidinones to be taken forward for further studies.

Tectona grandis Seed Mediated Green Synthesis of Silver Nanoparticles and Their Antibacterial Activity

Nanobiotechnology is a fast expanding scientific field with potential applications in life sciences and human health care. Silver is a precious metal that occurs naturally, most commonly as a mineral or in combination with other elements. Aqueous T. grandis plant seed extract was utilized in the current investigation as a reducing and capping agent in the biogenesis of silver nanoparticles. Nanoparticles were examined using different techniques like UV-visible spectral analysis, Fourier transform infrared spectra technique, X-ray diffraction technique, and transmission electron microscopy technique. The peak at 429 nm of the surface plasmon resonance by using UV-visible spectra, confirmed the synthesis of nanoparticles. Utilizing Fourier transforms infrared spectral analysis, the explicit functional groups that reduced silver nitrate to create silver nanoparticles in seed extract were found. X-ray diffraction analytical technique was utilized to found the crystalline nature and Face-centered cubic (FCC) configuration of green synthesized silver nanoparticles. Silver nanoparticles with sizes ranging from 32 to 62 nm are visible in images taken using transmission electron microscopy. Using disc diffusion technique, the generated silver nanoparticles showed remarkable antibacterial activity against selected organism, Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa. AgNPs demonstrated broad spectrum antibacterial action as a result at lower concentrations, and they may provide an effective therapeutic alternative in the future like, development of new antibacterial drugs. This research identified a quick and eco-friendly green synthetic method for producing stable silver nanoparticles. HIGHLIGHTS Preparation of synthesis from selected traditional medicinal plant Tectona grandis Bio synthesis and characterization of silver nanoparticles synthesized using Tectona grandis Seed extract and evaluate its antibacterial activity against selected pathogens The present study established a rapid, economical cheap way of synthesizing silver nanoparticles Synthesized plant mediated nanoparticles can be used against human pathogens acts as antimicrobial drug and have more medicinal applications GRAPHICAL ABSTRACT

Identification, Typing and Drug Resistance of Cronobacter spp. in Powdered Infant Formula and Processing Environment.

Cronobacter spp. is a food-borne pathogenic microorganism that can cause serious diseases such as meningitis, sepsis, and necrotizing colitis in infants and young children. Powdered infant formula (PIF) is one of the main contamination routes, in which the processing environment is an important source of pollution. In this investigation, 35 Cronobacter strains isolated from PIF and its processing environment were identified and typed by 16S rRNA sequencing and multilocus sequence typing (MLST) technology. A total of 35 sequence types were obtained, and three new sequence types were isolated for the first time. The antibiotic resistance was analyzed, showing that all isolates were resistant to erythromycin but sensitive to ciprofloxacin. Multi-drug resistant strains accounted for 68.57% of the total, among which Cronobacter strains with the strongest drug resistance reached 13 multiple drug resistance. Combined with transcriptomics, 77 differentially expressed genes related to drug resistance were identified. The metabolic pathways were deeply excavated, and under the stimulation of antibiotic conditions, Cronobacter strains can activate the multidrug efflux system by regulating the expression of chemotaxis-related genes, thus, secreting more drug efflux proteins to enhance drug resistance. The study of drug resistance of Cronobacter and its mechanism has important public health significance for the rational selection of existing antibacterial drugs, the development of new antibacterial drugs to reduce the occurrence of bacterial resistance, and the control and treatment of infections caused by Cronobacter.

Investigation of α,ω-Disubstituted Polyamine-Cholic Acid Conjugates Identifies Hyodeoxycholic and Chenodeoxycholic Scaffolds as Non-Toxic, Potent Antimicrobials

With the increased incidence of antibiotic resistance, the discovery and development of new antibacterials is of increasing importance and urgency. The report of the natural product antibiotic squalamine in 1993 has stimulated a lot of interest in the study of structurally simplified cholic acid-polyamine derivatives. We report the synthesis of a focused set of deoxycholic acid-polyamine conjugates and the identification of hyodeoxycholic acid derivatives as being potently active towards S. aureus MRSA and some fungal strains, but with no attendant cytotoxicity or hemolytic properties. Analogue 7e exhibited bactericidal activity towards a range of Gram-positive bacteria, while preliminary investigation of its mechanism of action ruled out the bacterial membrane as being a primary cellular target as determined using an ATP-release bioluminescence assay.

DNA Gyrase as a Target for Quinolones.

Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quinolone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or develop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics.

Anti-Vibrio parahaemolyticus compounds from Streptomyces parvus based on Pan-genome and subtractive proteomics.

Vibrio parahaemolyticus is a foodborne pathogen commonly found in seafood, and drug resistance poses significant challenges to its control. This study aimed to identify novel drug targets for antibacterial drug discovery. To identify drug targets, we performed a pan-genome analysis on 58 strains of V. parahaemolyticus genomes to obtain core genes. Subsequently, subtractive proteomics and physiochemical checks were conducted on the core proteins to identify potential therapeutic targets. Molecular docking was then employed to screen for anti-V. parahaemolyticus compounds using a in-house compound library of Streptomyces parvus, chosen based on binding energy. The anti-V. parahaemolyticus efficacy of the identified compounds was further validated through a series of experimental tests. Pangenome analysis of 58 V. parahaemolyticus genomes revealed that there were 1,392 core genes. After Subtractive proteomics and physiochemical checks, Flagellar motor switch protein FliN was selected as a therapeutic target against V. parahaemolyticus. FliN was modeled and docked with Streptomyces parvus source compounds, and Actinomycin D was identified as a potential anti-V. parahaemolyticus agent with a strong binding energy. Experimental verification confirmed its effectiveness in killing V. parahaemolyticus and significantly inhibiting biofilm formation and motility. This study is the first to use pan-genome and subtractive proteomics to identify new antimicrobial targets for V. parahaemolyticus and to identify the anti-V. parahaemolyticus effect of Actinomycin D. These findings suggest potential avenues for the development of new antibacterial drugs to control V. parahaemolyticus infections.

Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY

The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.