New Class Of Antibacterial Agents Research Articles

Plug-In Safe-by-Design Nanoinorganic Antibacterials.

Due to antimicrobial resistance and the adverse health effects that follow broad and inappropriate use of antibacterial agents, new classes of antibacterials with broad and strong bactericidal activity and safety for human use are urgently required globally, increasingly so with the onset of climate change. However, R&D in this field is known to be rarely profitable, unless a cost-effective, flexible, and convenient platform that ensures the production of workable candidate antibacterials can be developed. To address this issue, inorganic nanomaterials have been considered for their bactericidal activities, yet further investigations of composition crystalline modifications and/or surface biomaterial coatings are still required to provide effective and safe antibacterial nanoparticles. In this study, we developed a plug-in system comprising a spark plasma reactor and a flow heater under nitrogen gas flow to supply precursor inorganic nanoparticles (Cu-Te configuration) that can be modulated in-flight at different temperatures. From antibacterial and toxicological assays in both in vitro and in vivo models, bactericidal and toxicological profiles showed that the plug-in system-based platform can be used to identify key parameters for producing safe-by-design agents with antibacterial activity [>88% (in vitro) and >80% (in vivo) in antibacterial efficiency] and safety (>65% in in vitro viability and >60% in in vivo survival rate).

698. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Multidrug-Resistant Gram-Negative Bacilli

BackgroundMultidrug-resistant Gram-negative bacilli (MDRGNB) are emerging as a challenging cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (Figure 1) which facilitates transport to the periplasm are being developed that show promise against Gram-negative organisms including multidrug-resistant strains of E. coli, K. pneumoniae and P. aeruginosa.MethodsYU253434, an example of this new class of antibacterials, was investigated in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a representative panel comprising 15 strains each of E. coli, K. pneumoniae and P. aeruginosa, which contain extended-spectrum β-lactamase (ESBL) and/or carbapenemases genes.All studies were performed according to current Clinical & Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Ceftazidime breakpoints were arbitrability chosen as a reference for YU253434 (susceptibilities ≤4 μg/mL for Enterobacteriaceae and ≤8 μg/mL for P. aeruginosa).ResultsMIC testing (Figures 2–4) against E. coli showed 11 strains were YU253434 susceptible (compared with 6 for ceftazidime, and 3 for imipenem); against K. pneumoniae 13 strains were YU253434 susceptible (compared with 2 for ceftazidime and 6 for imipenem); against P. aeruginosa 10 strains were YU253434 susceptible (compared with 0 for both ceftazidime and imipenem). There appeared to be no correlation between YU253434 resistance and the presence of specific lactamase genes.ConclusionYU253434, a new generation oxopyrazole antibiotic, demonstrated promising in vitro potency against a panel of E. coli, K. pneumonia, and P. aeruginosa strains which contain ESBL and/or carbapenemases genes. Disclosures All authors: No reported disclosures.

687. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Acinetobacter spp.

Background Acinetobacter spp. resistant to common antibiotics have become a worrying cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (figure) which facilitates transport to the periplasm are being developed which show promise against Gram-negative organisms including Acinetobacter spp.MethodsYU253911, an example of this new class of antibacterials, was characterized in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a collection of 200 previously described (whole-genome sequencing) Acinetobacter isolates including 98 carbapenem-resistant A. baumannii strains. YU253911’s antimicrobial activity was also evaluated in combination with complementary PBP agents and β-lactamase inhibitors by MIC and disc diffusion testing. All studies were performed according to current Clinical and Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Breakpoints for ceftazidime were arbitrarily chosen as reference.ResultsUsing ceftazidime (breakpoint ≤8 μg/mL) as a comparator, 175 of the 200 Acinetobacter isolates were susceptible to YU253911, which possessed an MIC50 of 0.5 μg/mL and an MIC90 of 16 μg/mL. This compared favorably to all previously tested β-lactams including penicillins, cephalosporins, monobactams and carbapenems (MIC50s 2 to >16 μg/mL). Against the subset of carbapenem-resistant A. baumannii isolates, YU253911’s potency was similar with an MIC50 of 1 μg/mL. Genetic analysis showed β-lactamase genes, including OXA-23 and other carbapenemases, were common in both YU253911-resistant and susceptible strains.ConclusionYU253911 demonstrates promising in vitro potency against a collection of Acinetobacter isolates and compares favorably to β-lactam antibiotics. Understanding interactions with PBP agents and β lactamase inhibitors is being explored as well as further studies on the mechanism of resistance. Disclosures All authors: No reported disclosures.

Design and synthesis of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives as antibacterial agents based on cajaninstilbene acid scaffold hopping.

The prevalence of multidrug resistance among clinically significant bacterial pathogens underlines a critical need for the development of new classes of antibacterial agents with novel structural scaffolds. Cajaninstilbene acid (CSA), which is isolated from pigeonpea leaves, has shown potent antibacterial activity. In this study, a series of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives derived from CSA were designed and synthesized, and their antibacterial activities were evaluated. Several synthesized compounds exhibit better antibacterial activity than CSA against Staphylococcus aureus, Staphylococcus epidermidis, and two strains of methicillin-resistant S. aureus. Meanwhile, the results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays illustrate the good selectivity between bacteria and normal cells of the most active compounds 6u and 6v. Furthermore, well combinations with bacterial RNA polymerase of 6u arising from docking study imply the possible mechanism of antibacterial activity of these synthetic compounds.

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents.

The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g. E. Coli, K. pneumoniae and S. aureus, have high resistance vs the last generations of cephalosporins, carbapenems and fluoroquinolones. During the past decades, only few successful efforts to develop and launch new antibacterial medications have been performed. This study aims to identify new class of antibacterial agents using novel high-throughput screening technique. We have designed library containing 125K compounds not similar in structure (Tanimoto coeff.< 0.7) to that published previously as antibiotics. The HTS platform based on double reporter system pDualrep2 was used to distinguish between molecules able to block translational machinery or induce SOS-response in a model E. coli system. MICs for most active chemicals in LB and M9 medium were determined using broth microdilution assay. In an attempt to discover novel classes of antibacterials, we performed HTS of a large-scale small molecule library using our unique screening platform. This approach permitted us to quickly and robustly evaluate a lot of compounds as well as to determine the mechanism of action in the case of compounds being either translational machinery inhibitors or DNA-damaging agents/replication blockers. HTS has resulted in several new structural classes of molecules exhibiting an attractive antibacterial activity. Herein, we report as promising antibacterials. Two most active compounds from this series showed MIC value of 1.2 (5) and 1.8 μg/mL (6) and good selectivity index. Compound 6 caused RFP induction and low SOS response. In vitro luciferase assay has revealed that it is able to slightly inhibit protein biosynthesis. Compound 5 was tested on several archival strains and exhibited slight activity against gram-negative bacteria and outstanding activity against S. aureus. The key structural requirements for antibacterial potency were also explored. We found, that the unsubstituted carboxylic group is crucial for antibacterial activity as well as the presence of bulky hydrophobic substituents at phenyl fragment. The obtained results provide a solid background for further characterization of the 5'- (carbonylamino)-2,3'-bithiophene-4'-carboxylate derivatives discussed herein as new class of antibacterials and their optimization campaign.

The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus.

The quinazolinones are a new class of antibacterials with in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA). The quinazolinones target cell wall biosynthesis and have a unique mechanism of action by binding to the allosteric site of penicillin-binding protein 2a (PBP 2a). We investigated the potential for synergism of a lead quinazolinone with several antibiotics of different classes using checkerboard and time-kill assays. The quinazolinone synergized with β-lactam antibiotics. The combination of the quinazolinone with commercial piperacillin-tazobactam showed bactericidal synergy at sub-MICs of all three drugs. We demonstrated the efficacy of the triple-drug combination in a mouse MRSA neutropenic thigh infection model. The proposed mechanism for the synergistic activity in MRSA involves inhibition of the β-lactamase by tazobactam, which protects piperacillin from hydrolysis, which can then inhibit its target, PBP 2. Furthermore, the quinazolinone binds to the allosteric site of PBP 2a, triggering the allosteric response. This leads to the opening of the active site, which, in turn, binds another molecule of piperacillin. In other words, PBP 2a, which is not normally inhibited by piperacillin, becomes vulnerable to inhibition in the presence of the quinazolinone. The collective effect is the impairment of cell wall biosynthesis, with bactericidal consequence. Two crystal structures for complexes of the antibiotics with PBP 2a provide support for the proposed mechanism of action.

&lt;I&gt;N&lt;/I&gt;-пиридинил-замещенные амиды карбоксипиперидинов как новый класс ингибиторов трансляции прокариот

Выполненный высокопроизводительный скрининг продемонстрировал новый класс антибактериальных соединений на основе N-пиридинил-замещенных амидов пара- и мета-карбоксипиперидинов. Конструкция с 2 репортерными генами RFP и Katushka2S позволяет выявлять соединения, ингибирующие трансляцию белка против ингибирования биосинтеза ДНК. Некоторые соединения из данного класса продемонстрировали антибактериальную активность, ингибируя трансляцию. Наиболее перспективное соединение имеет значение МИК, равное 12 мкг/мл. Таким образом, этот класс молекул может стать ценной отправной точкой для разработки новых соединений с более высокой антибактериальной активностью и селективностью.

Antibacterial activity of water soluble dye capped zinc oxide nanoparticles synthesised from waste Zn–C battery

Antibacterial activity of functionalized ZnO nanoparticles synthesized from waste Zn–C battery by microwave method was investigated, water soluble 1-(carboxymethyl)-4-[(E)-2-(3-methoxy-4-methylphenyl)ethenyl] pyridin-1-ium photosensitizer was used as capping agent to control the size of nanoparticle. The characterization of the samples was done with the help of UV–visible spectroscopy, FTIR, SEM–EDS and XRD. The nanoparticles have hexagonal wurtzite structure with a mean diameter of 19.7 nm for 3% dye capped nanoparticle and 30.6 nm for uncapped nanoparticle and are composed by a mixture of small crystallites and disordered ZnO particles. Capped ZnO nanoparticles showed high antibacterial (tested on E. coli and B. subtilis) activities compared to that of uncapped nanoparticles under the same experimental conditions. This novel water soluble dye capped ZnO nanoparticles emerged as excellent antibacterial agent, the results show minimum inhibitory concentration of 0.39 and 1.56 for B. subtilis and E. coli and highest zone of inhibition was at concentration of 5 mg/ml. The bioactivity showed dye capped nanoparticle to be new class of antibacterial agent.

Enantioselective recognition of sutezolid by cyclodextrin modified non-aqueous capillary electrophoresis and explanation of complex formation by means of infrared spectroscopy, NMR and molecular modelling

A method for the enantioseparation of sutezolid, the next analogue after linezolid and tedizolid, belonging to the truly new class of antibacterial agents, the oxazolidinones, was developed based on non-aqueous capillary electrophoresis (NACE), using a single isomer of cyclodextrins as a chiral pseudophase. During the experiment, the enantioseparation of sutezolid together with its predecessor, linezolid, both weak base antibacterial agents, was evaluated using anionic single-isomers of cyclodextrins from hydrophilic, up to hydrophobic: heptakis-(2,3-dihydroxy-6-sulfo)-β-cyclodextrin, heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD), as well as heptakis-(2,3-dimethyl-6-sulfo)-β-cyclodextrin (HDMS-β-CD), respectively. Based on the observed results, the cyclodextrins, HDAS-β-CD and HDMS-β-CD which carry the acetyl and methyl groups at the C2 and C3 positions, respectively, provided the baseline separation of sutezolid enantiomers. However, HDMS-β-CD led to a reversal of enantiomer migration order (EMO) in comparison to HDAS-β-CD. Instead, enantiomers of linezolid were separated only by HDMS-β-CD. During the experiments, different organic solvents and their mixtures in various ratios were tested. The selectivity and separation efficiency were critically affected by the nature of the buffer system, the type of organic solvent, and the concentrations of trifluoroacetic acid (TFA) in the NACE buffer system.Focusing on the desired EMO in which the eutomers (S)-sutezolid and (S)-linezolid migrated last, the highest enantioresolution using the NACE method was achieved at normal polarity mode with 45 mM HDMS-β-CD dissolved in MeOH/ACN (85:15, v/v) containing 200 mM TFA/20 mM ammonium formate. Moreover, infrared spectroscopy, NMR and molecular modelling were investigated to provide information about complex formation.

Secondary metabolites overproduction through transcriptional gene cluster refactoring

We present a random rational approach enabling the construction of overproducing strains in two steps. The approach first involves creating a library of clusters of interest, in which native promoters are substituted with randomly generated constitutive synthetic promoters, and then expressing this library in an appropriate host strain. This strategy is fast, easy to use, accounts for the architecture of a cluster and completely decouples the expression of a gene cluster from complex native regulatory networks. The strategy was applied to improve the production of a macrocyclic peptide, bottromycin, which possesses antibacterial activity against multidrug-resistant bacteria and is a blueprint for a new class of antibacterials. We successfully optimized the expression of genes in operons and created several variants of the bottromycin gene cluster that provide 5–50 fold higher titres of bottromycin than the natural one, thus resulting in the identification of several new bottromycin derivatives not previously described. Moreover, due to the higher bottromycin yield, bottromycin derivatization was performed via the biosynthetic engineering of the gene cluster. The abovementioned features make this generic strategy a promising tool for the overproduction of known secondary metabolites and the activation of silent secondary metabolites in Actinobacteria.

Design and characterization of novel Al-doped ZnO nanoassembly as an effective nanoantibiotic

Nanoantibiotics are the new class of antibacterial agents that can be an alternative to the conventional antibiotics, which are expensive and require lengthy synthesis procedures. In view of such importance of nanoantibiotics, in the present study, we have systematically designed Al doped ZnO (AZO) via a co-precipitation method. ZnO nanoparticles own decent bactericidal activity against clinically isolated bacterial species, however, its bactericidal concentrations are compromised. To enhance the antibacterial efficiency of ZnO, different concentrations of Al was doped into ZnO lattice to design AZO nanorods, which were characterized using XRD, RAMAN, FESEM, DSC/TGA and Zetasizer. The XRD data confirmed a hexagonal wurtzite structure of AZO, while the bimetallic composition of the AZO was evaluated by RAMAN spectra and EDX. The average diameters of AZO nanorods were less than 100 nm. The zeta potential of ZnO was enhanced from 6.17 ± 0.5 to 22.7 ± 0.3 mV at 15% doping of Al. The biomedical value and commercial applicability of AZO nanorods were evaluated in terms of its biocompatibility using L929 mouse fibroblast and the antibacterial activity against Escherichia coli and Enterococcus hirae. The antibacterial activity was found to be significantly enhanced to ~ 19 times with MIC values of 14.33 ± 0.20 and 14.68 ± 0.20 µg/ml for AZO (15% doping) as compared to 254.88 ± 3.0 and 338.14 ± 9.0 µg/ml for ZnO against E. coli and E. hirae, respectively. The antibacterial mechanism was found to be electrostatic interaction between bacterial cell and AZO, followed by the intracellular accumulation of the Zn2+ ions. The release of Zn2+ ions from AZO was found to be kinetic controlled (diffusion limited). The synthesized nanorods showed excellent biocompatibility with more than 95 ± 3% of cell viability up to 6 days even at higher concentrations, indicating its promise for in vivo analysis. Hence, this study designates AZO as a plausible nanoantibiotic and unlocks its access for various other biomedical applications.

Tuning the biological activity of cationic anthraquinone analogues specifically toward Staphylococcus aureus

Development of new antibacterial agents against drug resistant bacteria is an imminent task, especially against methicillin-resistant Staphylococcus aureus (MRSA). While MRSA can still be treated with broad spectrum antibiotics, the use of which often leads to the disruption of normal microbial flora leading to Clostridium difficile infection (CDI). Herein, a new class of antibacterial agent, cationic anthraquinone analogues specifically against MRSA, has been developed. Through the variation and optimization of substituents, these agents are selective toward MRSA, and not Gram negative bacteria which may avoid the problem of CDI. In addition, newly discovered lead compounds also show significantly reduced cytotoxicity against normal mammalian cells than cancerous cells. This interesting finding can alleviate the toxicity and side effect problems often associate with the use of antibiotics.

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents.

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (−9.65 and −10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

Pseudomonas aeruginosa Quorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives.

Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multidrug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to coordinate virulence gene expression, is a potential target that has been intensively investigated over the past decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems ( las, rhl, and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.

Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety

Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1 μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.

A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.

Imidazopyrazinones (IPYs) are a new class of compounds that target bacterial topoisomerases as a basis for their antibacterial activity. We have characterized the mechanism of these compounds through structural/mechanistic studies showing they bind and stabilize a cleavage complex between DNA gyrase and DNA (‘poisoning’) in an analogous fashion to fluoroquinolones, but without the requirement for the water–metal–ion bridge. Biochemical experiments and structural studies of cleavage complexes of IPYs compared with an uncleaved gyrase–DNA complex, reveal conformational transitions coupled to DNA cleavage at the DNA gate. These involve movement at the GyrA interface and tilting of the TOPRIM domains toward the scissile phosphate coupled to capture of the catalytic metal ion. Our experiments show that these structural transitions are involved generally in poisoning of gyrase by therapeutic compounds and resemble those undergone by the enzyme during its adenosine triphosphate-coupled strand-passage cycle. In addition to resistance mutations affecting residues that directly interact with the compounds, we characterized a mutant (D82N) that inhibits formation of the cleavage complex by the unpoisoned enzyme. The D82N mutant appears to act by stabilizing the binary conformation of DNA gyrase with uncleaved DNA without direct interaction with the compounds. This provides general insight into the resistance mechanisms to antibiotics targeting bacterial type II topoisomerases.

A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.

Imidazopyrazinones (IPYs) are a new class of compounds that target bacterial topoisomerases as a basis for their antibacterial activity. We have characterized the mechanism of these compounds through structural/mechanistic studies showing they bind and stabilize a cleavage complex between DNA gyrase and DNA (‘poisoning’) in an analogous fashion to fluoroquinolones, but without the requirement for the water–metal–ion bridge. Biochemical experiments and structural studies of cleavage complexes of IPYs compared with an uncleaved gyrase–DNA complex, reveal conformational transitions coupled to DNA cleavage at the DNA gate. These involve movement at the GyrA interface and tilting of the TOPRIM domains toward the scissile phosphate coupled to capture of the catalytic metal ion. Our experiments show that these structural transitions are involved generally in poisoning of gyrase by therapeutic compounds and resemble those undergone by the enzyme during its adenosine triphosphate-coupled strand-passage cycle. In addition to resistance mutations affecting residues that directly interact with the compounds, we characterized a mutant (D82N) that inhibits formation of the cleavage complex by the unpoisoned enzyme. The D82N mutant appears to act by stabilizing the binary conformation of DNA gyrase with uncleaved DNA without direct interaction with the compounds. This provides general insight into the resistance mechanisms to antibiotics targeting bacterial type II topoisomerases.

C8-Linked Pyrrolobenzodiazepine Monomers with Inverted Building Blocks Show Selective Activity against Multidrug Resistant Gram-Positive Bacteria.

Antimicrobial resistance has become a major global concern. Development of novel antimicrobial agents for the treatment of infections caused by multidrug resistant (MDR) pathogens is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents initially discovered and isolated from natural sources. Recently, C8-linked PBD biaryl conjugates have been shown to be active against some MDR Gram-positive strains. To explore the role of building block orientations on antibacterial activity and obtain structure activity relationship (SAR) information, four novel structures were synthesized in which the building blocks of previously reported compounds were inverted, and their antibacterial activity was studied. The compounds showed minimum inhibitory concentrations (MICs) in the range of 0.125-32 μg/mL against MDR Gram-positive strains with a bactericidal mode of action. The results showed that a single inversion of amide bonds reduces the activity while the double inversion restores the activity against MDR pathogens. All inverted compounds did not stabilize DNA and lacked eukaryotic toxicity. The compounds inhibit DNA gyrase in vitro, and the most potent compound was equally active against both wild-type and mutant DNA gyrase in a biochemical assay. The observed activity of the compounds against methicillin resistant S.aureus (MRSA) strains with equivalent gyrase mutations is consistent with gyrase inhibition being the mechanism of action in vivo, although this has not been definitively confirmed in whole cells. This conclusion is supported by a molecular modeling study showing interaction of the compounds with wild-type and mutant gyrases. This study provides important SAR information about this new class of antibacterial agents.

Design and Synthesis of Malonamide Derivatives as Antibiotics against Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious threat to humans. Most existing antimicrobial drugs, including the β-lactam and quinoxiline classes, are not effective against MRSA. In this study, we synthesized 24 derivatives of malonamide, a new class of antibacterial agents and potentiators of classic antimicrobials. A derivative that increases bacterial killing and biofilm eradication with low cell toxicity was created.

Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria.

New antibiotics are urgently needed to address multidrug-resistant (MDR) bacteria. Herein we report that second-generation (G2) peptide dendrimers bearing a fatty acid chain at the dendrimer core efficiently kill Gram-negative bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii, two of the most problematic MDR bacteria worldwide. Our most active dendrimer TNS18 is also active against Gram-positive methicillin-resistant Staphylococcus aureus. Based on circular dichroism and molecular dynamics studies, we hypothesize that TNS18 adopts a hydrophobically collapsed conformation in water with the fatty acid chain backfolded onto the peptide dendrimer branches and that the dendrimer unfolds in contact with the membrane to expose its lipid chain and hydrophobic residues, thereby facilitating membrane disruption leading to rapid bacterial cell death. Dendrimer TNS18 shows promising in vivo activity against MDR clinical isolates of A. baumannii and Escherichia coli, suggesting that lipidated peptide dendrimers might become a new class of antibacterial agents.