Rapid Bactericidal Effect Research Articles

Comparative in vitro activity of bacteriophage endolysin HY-133 against Staphylococcus aureus attached to vascular graft surface.

Novel strategies are needed for combating Staphylococcus aureus biofilm in vascular graft infections. We investigated the in vitro activity of bacteriophage endolysin HY-133, daptomycin and rifampin against S. aureus attached to vascular graft surface. Daptomycin showed rapid bactericidal effect on surface-associated S. aureus, while the activity of HY-133 on graft surface-adherent cells was moderate and rifampin did not achieve bactericidal effect. Even in the highest concentrations, all antimicrobials used failed in a complete eradication of the surface-adherent bacteria.

Antibacterial Activity of Terpenes and Terpenoids Present in Essential Oils.

Background: The antimicrobial activity of essential oils has been reported in hundreds of studies, however, the great majority of these studies attribute the activity to the most prevalent compounds without analyzing them independently. Therefore, the aim was to investigate the antibacterial activity of 33 free terpenes commonly found in essential oils and evaluate the cellular ultrastructure to verify possible damage to the cellular membrane. Methods: Screening was performed to select substances with possible antimicrobial activity, then the minimal inhibitory concentrations, bactericidal activity and 24-h time-kill curve studies were evaluated by standard protocols. In addition, the ultrastructure of control and death bacteria were evaluated by scanning electron microscopy. Results: Only 16 of the 33 compounds had antimicrobial activity at the initial screening. Eugenol exhibited rapid bactericidal action against Salmonella enterica serovar Typhimurium (2 h). Terpineol showed excellent bactericidal activity against S. aureus strains. Carveol, citronellol and geraniol presented a rapid bactericidal effect against E. coli. Conclusions: The higher antimicrobial activity was related to the presence of hydroxyl groups (phenolic and alcohol compounds), whereas hydrocarbons resulted in less activity. The first group, such as carvacrol, l-carveol, eugenol, trans-geraniol, and thymol, showed higher activity when compared to sulfanilamide. Images obtained by scanning electron microscopy indicate that the mechanism causing the cell death of the evaluated bacteria is based on the loss of cellular membrane integrity of function. The present study brings detailed knowledge about the antimicrobial activity of the individual compounds present in essential oils, that can provide a greater understanding for the future researches.

Pathogenetic therapy of rhinosinusites in the practice of otorhinolaryngologist

An important and topical problem of modern otorhinolaryngology is the search for effective and safe medicines for the treatment of bacterial sinusitis, which is one of the most common human diseases, and this problem is becoming more and more acute every year. When prescribing antibacterial therapy for patients with acute and chronic rhinosinusitis, an otorhinolaryngologist should be sure that the drug has a rapid bactericidal effect, the spectrum of its activity includes most of the possible pathogens, and pharmacodynamics of the drug contribute to its accumulation in the focus of the pathological process.

Bactericidal effects and accelerated wound healing using Tb4O7 nanoparticles with intrinsic oxidase-like activity

BackgroundNanomaterials that exhibit intrinsic enzyme-like characteristics have shown great promise as potential antibacterial agents. However, many of them exhibit inefficient antibacterial activity and biosafety problems that limit their usefulness. The development of new nanomaterials with good biocompatibility and rapid bactericidal effects is therefore highly desirable. Here, we show a new type of terbium oxide nanoparticles (Tb4O7 NPs) with intrinsic oxidase-like activity for in vitro and in vivo antibacterial application.ResultsWe find that Tb4O7 NPs can quickly oxidize a series of organic substrates in the absence of hydrogen peroxide. The oxidase-like capacity of Tb4O7 NPs allows these NPs to consume antioxidant biomolecules and generate reactive oxygen species to disable bacteria in vitro. Moreover, the in vivo experiments showed that Tb4O7 NPs are efficacious in wound-healing and are protective of normal tissues.ConclusionsOur results reveal that Tb4O7 NPs have intrinsic oxidase-like activity and show effective antibacterial ability both in vitro and in vivo. These findings demonstrate that Tb4O7 NPs are effective antibacterial agents and may have a potential application in wound healing.

Bactericidal activity of bacteriophage endolysin HY-133 against Staphylococcus aureus in comparison to other antibiotics as determined by minimum bactericidal concentrations and time-kill analysis

Methicillin-resistant Staphylococcus aureus (MRSA) decolonization is expensive and time consuming, and new agents are necessary due to increasing resistance rates. The administration of bacteriophages or particularly their endolysins may offer an alternative treatment strategy and could provide a solution to overcome the selection pressure due to classical antibiotics. Here, the bactericidal activity was characterized for the recombinant chimeric bacteriophage endolysin HY-133 in comparison to other antimicrobials. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined for 2 reference strains, 24 clinical MRSA and methicillin-susceptible S. aureus (MSSA) isolates, as well as 6 isolates with high-level mupirocin resistance. Additionally, HY-133 activity against bacteria in stationary or exponential growth phase was compared in 12 isolates. Time-kill curves were performed with 2 representative isolates to investigate the pharmacodynamics until 48-h incubation time. All experiments were performed in comparison to daptomycin and mupirocin. The MIC50/90 and MBC50/90 values were in the range 0.12–0.5 mg/L for all 3 growth conditions comparable to daptomycin with 0.5/0.5 mg/L, respectively. The MBC was almost always equal the MIC and without considerable differences between MSSA and MRSA. Time-kill curves revealed a rapid bactericidal effect of HY-133 within the first 2 h, similar to daptomycin. Even with low concentrations, the recombinant endolysin HY-133 was highly active against all tested MSSA and MRSA isolates including mupirocin-resistant isolates. The application of this alternative agent may offer a future strategy for MRSA/MSSA decolonization and, potentially, for treatment purposes.

Purification and Characterization of Pasteuricin Produced by Staphylococcus pasteuri RSP-1 and Active against Multidrug-Resistant Staphylococcus aureus

Staphylococcus aureus is an important pathogen implicated in various diseases, including staphylococcal food poisoning. Bacteriocins are considered safe and effective antimicrobial substances for the prevention of the growth of pathogenic bacteria. In this article, we describe the purification and characterization of pasteuricin, a novel bacteriocin produced by Staphylococcus pasteuri RSP-1. A cell-free supernatant of S. pasteuri RSP-1 exerted strong antimicrobial activity against staphylococci, including methicillin-resistant S. aureus (MRSA), and gram-positive bacteria. The loss of antimicrobial activity upon treatment with proteolytic enzymes confirmed the proteinaceous nature of pasteuricin. A rapid and pronounced bactericidal effect of pasteuricin was confirmed by a live-dead bacterial viability assay. To our knowledge, pasteuricin is the first reported S. pasteuri bacteriocin that inhibits S. aureus. Because pasteuricin is characterized by strong antimicrobial activity and high stability, it has potential as an alternative antimicrobial agent to antibiotics.

Antimicrobial mechanism and the effect of atmospheric pressure N2 plasma jet on the regeneration capacity of Staphylococcus aureus biofilm

This study systematically assessed the inactivation mechanism on Staphylococcus aureus biofilms by a N2 atmospheric-pressure plasma jet and the effect on the biofilm regeneration capacity from the bacteria which survived, and their progenies. The total bacterial populations were 7.18 ± 0.34 log10 CFU ml−1 in biofilms and these were effectively inactivated (>5.5-log10 CFU ml−1) within 30 min of exposure. Meanwhile, >80% of the S. aureus biofilm cells lost their metabolic capacity. In comparison, ∼20% of the plasma-treated bacteria entered a viable but non-culturable state. Moreover, the percentage of membrane-intact bacteria declined to ∼30%. Scanning electron microscope images demonstrated cell shrinkage and deformation post-treatment. The total amount of intracellular reactive oxygen species was observed to have significantly increased in membrane-intact bacterial cells with increasing plasma dose. Notably, the N2 plasma treatment could effectively inhibit the biofilm regeneration ability of the bacteria which survived, leading to a long-term phenotypic response and dose-dependent inactivation effect on S. aureus biofilms, in addition to the direct rapid bactericidal effect.

Efficacy of chimeric ectolysin P128 in drug-resistant Staphylococcus aureus bacteraemia in mice.

P128 is a recombinant chimeric ectolysin with potent antistaphylococcal activity. P128 was evaluated as monotherapy and in combination with two standard-of-care (SoC) antibiotics, vancomycin and daptomycin, in mouse models of Staphylococcus aureus bacteraemia. Healthy BALB/c mice were challenged (intraperitoneally) with 109 cfu of MRSA strain COL or USA300 and treated with a single dose of P128 (0.2-10 mg/kg). Drug synergy was tested using a single dose of P128 (0.2 or 2.5 mg/kg) along with sub-therapeutic dose levels of vancomycin (27.5 or 55 mg/kg) or daptomycin (12.5 mg/kg). Bacterial load was checked in peritoneal fluid and in blood, at different time intervals. Synergy against drug-resistant strains was tested using the P128/vancomycin combination against vancomycin-resistant S. aureus (VRSA). In MRSA bacteraemia, P128, vancomycin and daptomycin monotherapy resulted in 31%, 46% and 46% survival, respectively. The P128/vancomycin and P128/daptomycin combinations afforded increased survival of 85% and 88%, respectively. P128 showed a rapid bactericidal effect with a reduction of cfu in both the peritoneal fluid and the blood within 1 h. In VRSA bacteraemia, a mouse-equivalent therapeutic dose of vancomycin (110 mg/kg) failed to rescue animals. P128 (1-20 mg/kg) as monotherapy resulted in dose-dependent efficacy. Survival (37%) with 2.5 mg/kg P128 increased to 63% with the P128/vancomycin combination. P128 exerted a rapid bactericidal effect in vivo and rescued animals from fatal invasive MRSA and VRSA infections. P128/SoC antibiotic combinations exerted a synergistic effect. P128 restored the susceptibility of VRSA to vancomycin. P128 is a novel, potent therapeutic agent for antibiotic-resistant, systemic S. aureus infections.

Sa1067 IMMEDIATE PRE-INSERTION ALCOHOL FLUSH AND FLEX PROTOCOL (AFFP) FOR ADDITIONAL DECONTAMINATION AT ERCP AND EUS: EXPERIENCE WITH 4671 CASES

Serious systemic infections due to carbapenem resistant enterobacteria (CRE) and other bacteria have been traced to inadequately disinfected elevator equipped endoscopies (EEE). The potential reason for residual microbes appear to be multifactorial including errors in mechanical or AER cleaning, endoscope wear or design issues, or post-cleaning contamination. 70% isopropyl alcohol has been proven to be an effective medical hand sanitizer due to its rapid bactericidal effect. Since 6/2015, we have been using a standard isopropyl alcohol based decontamination protocol just before endoscope insertion to reduce the risk of unexpected residual bacteria. All EEE are first cleaned by OEM guidelines supervised by a reprocessing specialist. In the endoscopy suite, just before insertion, ERCP and EUS endoscopes are flushed with 60cc of 70% isopropyl alcohol while flexing the elevators repeatedly. After suctioning back the alcohol, sterile water is suctioned to clear the channel of residual. Surveillance cultures are performed by CDC guidelines on two of our twelve elevator endoscopes weekly or biweekly after a minimum “hang time” of twelve hours. All cultured EEE are then held in quarantine pending results. Positive cultures are reprocessed and recultured. Effectiveness of this protocol is evaluated by hospital epidemiology case research and CRE point prevalence monitoring. From the onset of the AFFP in 6/2015 to 11/2017, 4671 cases (3277 ERCP and 1394 EUS) have been performed. Surveillance cultures were positive in 8/309 (2.6%) contaminants 5 (skin flora), non-pathogens 2 (Corynebacterium) and pathogens 1 (Enterococcus faecium (broth only)) or 1/309 (0.32%). Of note, this one pathogen was prior to improvements in CDC culture guidelines, and new OEM disinfection training. No EEE associated infections have been identified despite the presence of drug resistant organisms including CRE in our hospital. The source of occasional residual microbes after OEM cleaning documented by CDC culture techniques remains unclear.

Bioinspired Antimicrobial Nanodots with Amphiphilic and Zwitterionic-like Characteristics for Combating Multidrug-Resistant Bacteria and Biofilm Removal

Inspired by the natural antimicrobial peptides, we have developed a benign antimicrobial nanodot (BAM dot) via a simple one-step hydrothermal synthesis. The BAM dot possesses the unique properties of both nanoparticles and biomaterials, leading to excellent antibacterial properties with a high therapeutic index. Specifically, this BAM dot has ultrasmall size (3.83 ± 0.73 nm) with a charged neutral surface. They also exhibited amphiphilic and zwitterionic-like properties, which enabled effective bacteria membrane permeabilization, leading to a rapid bactericidal effect and significant biofilm removal. This study opens up new opportunities to design effective bioinspired nanomaterials for combating superbugs against drug resistance and their related applications.

Cetylpyridinium chloride direct spray treatments reduce Salmonella on cantaloupe rough surfaces.

Cetylpyridinium chloride (CPC) solutions (0, 0.5, or 1.0%) were applied to cantaloupe (“Athena” and “Hale's Best Jumbo” cultivars) rind plugs, either before or after inoculation with a broth culture of Salmonella Michigan (109 CFU/mL) and held at 37°C for 1 or 24 hr. Rind plugs were diluted, shaken, and sonicated, and solutions were enumerated. Texture quality and color were evaluated over 14 days storage at 4°C after 0 and 1% CPC spray applications. A 0.5 or 1.0% (vol/vol) application of CPC after Salmonella reduced the pathogen levels between 2.34 log CFU/mL and 5.16 log CFU/mL in comparison to the control (p < .01). No differences were observed in the firmness and color of 1% CPC treated cantaloupes. Salmonella concentrations on cantaloupes, treated with 1.0% CPC, were lower after 1 hr storage as compared to 24 hr. And, Salmonella on “Athena” surfaces were more susceptible to CPC spray treatments than on “Hale's Best Jumbo.”Practical applicationsCetylpyridinium chloride (CPC) is the active ingredient of some antiseptic oral mouth rinses, and has a broad antimicrobial spectrum with a rapid bactericidal effect on gram‐positive pathogens. The spray application of CPC solutions to cantaloupe may reduce the level of Salmonella surface contamination during production from irrigation water and manure fertilizers and, during food processing by contaminated equipment and food handlers. Since the surfaces of cantaloupes are highly rough or irregular, bacteria can easily attach to these surfaces and become difficult to remove. Appropriate postharvest washing and sanitizing procedures are needed that can help control Salmonella and other pathogens on melons, especially on cantaloupes with nested surfaces. A direct surface spray application of CPC may be an alternative antimicrobial postharvest treatment to reduce pathogen contamination of cantaloupe melons, while providing an alternative to chlorine‐based solutions.

Studies on the Antibacterial Activity and Mechanism of Antimicrobial Peptides Against Drug-Resistant Bacteria.

Antibiotic resistance is a growing threat to human health. More than anything else, multidrug-resistant gram-negative bacteria pose the biggest challenge to healthcare, which is predominantly due to the lack of effective therapeutic options. In the present study, we investigated the activities of peptides HX-12A, HX-12B and HX-12C against MDRAB and MDRKP isolates in vitro. Those three peptides displayed high antibacterial activities and rapid bactericidal effects against MDRAB and MDRKP isolates. Additionally, the peptides retained their activity even being present in pH 6.8 and 8.0, salt (NaCl 100 mM, CaCl2 1 mM, MgCl2 1 mM) or human serum (5%), especially peptide HX-12C. Moreover, the killing kinetics and transmission electron microscopy results suggested that the possible sterilization mechanism of peptides is to destroy the cell membrane, which makes it more difficult for bacteria to develop resistance. Thus, these three peptides may be developed into new antimicrobial agents.

Effect of the adhesion of Ag coatings on the effectiveness and durability of antibacterial properties

The adhesion force between metal-based antibacterial coatings and polymer substrate decides the effectiveness and durability of antibacterial performance. In this study, the silicone rubber substrate was modified by molecular bridge, i.e., polyvinylpyrrolidone, chitosan and (3-mercaptopropyl) trimethoxysilane, to provide “anchors” which captured Ag+ during electroless plating, and Ag coatings were resultantly produced. Different molecular bridge offered different adhesion. The spread plate counting, fluorescent staining assay and bacterial growth kinetics test showed that the antibacterial and anti-biofilm performance against Escherichia coli and Staphylococcus aureus was directly related to coating–substrate adhesion strength. A relative weaker adhesion resulted in rapid bactericidal and bacteria growth inhibition effect, and vice versa. The inductively coupled plasma atomic emission spectrometry indicated that relative weak adhesion provided fast Ag+ release, and strong adhesion gave lower Ag+ cumulative concentration, which may be attributed to different bonding strength. The coatings displayed sustained-release kinetics with the maximum cumulative Ag+ concentration of only 0.45 mg/L after 45 days of immersion in PBS solution, which was far below the human cell toxicity concentration. Nevertheless, all tested Ag coatings exhibited effective and long-lasting antibacterial properties. The tailored adhesion and consequent different antibacterial effect provided a choice for clinical applications.

Morphological bactericidal fast-acting effects of peracetic acid, a high-level disinfectant, against Staphylococcus aureus and Pseudomonas aeruginosa biofilms in tubing

BackgroundThe bactericidal effect of disinfectants against biofilms is essential to reduce potential endoscopy-related infections caused by contamination. Here, we investigated the bactericidal effect of a high-level disinfectant, peracetic acid (PAA), against Staphylococcus aureus and Pseudomonas aeruginosa biofilm models in vitro.MethodsS. aureus and P. aeruginosa biofilms were cultured at 35 °C for 7 days with catheter tubes. The following high-level disinfectants (HLDs) were tested: 0.3% PAA, 0.55% ortho-phthalaldehyde (OPA), and 2.0% alkaline-buffered glutaraldehyde (GA). Biofilms were exposed to these agents for 1–60 min and observed after 5 min and 30 min by transmission and scanning electron microscopy. A Student’s t test was performed to compare the exposure time required for bactericidal effectiveness of the disinfectants.ResultsPAA and GA were active within 1 min and 5 min, respectively, against S. aureus and P. aeruginosa biofilms. OPA took longer than 10 min and 30 min to act against S. aureus and P. aeruginosa biofilms, respectively (p < 0.01). Treatment with PAA elicited changes in cell shape after 5 min and structural damage after 30 min.ConclusionsAmongst the HLDs investigated, PAA elicited the most rapid bactericidal effects against both biofilms. Additionally, treatment with PAA induced morphological alterations in the in vitro biofilm models, suggesting that PAA exerts fast-acting bactericidal effects against biofilms associated with endoscopy-related infections. These findings indicate that the exposure time for bactericidal effectiveness of HLDs for endoscope reprocessing in healthcare settings should be reconsidered.

Antibacterial activity of extract and fractions from branches of Protium spruceanum and cytotoxicity on fibroblasts

The crude ethanol extract (CEE) and fractions from branches of Protium spruceanum were subjected to antibacterial and cytotoxicity assays. Compounds of the most active fraction were identified by GC-MS and LC-MS. CEE was active against 19 bacteria and the ethyl acetate fraction (EAF) showed the lowest minimum bactericidal concentration (MBC 0.3–80.0 mg/mL). Through time-kill assay was observed that EAF induced rapid bactericidal effect against Staphylococcus saprophyticus. The cytotoxicity tests against L929 fibroblasts showed great potential of EAF on the treatment of infections caused by five bacteria (MBC < IC50). The results provide in vitro scientific support to the possible application of branches of P. spruceanum as antimicrobial agent that may contribute for treatment of infections.

Antibacterial Effect of Synthetic Peptide LyeTxI and LyeTxI/β-Cyclodextrin Association Compound Against Planktonic and Multispecies Biofilms of Periodontal Pathogens.

Antimicrobial peptides (AMPs) have shown rapid and potent effect against planktonic bacteria. However, control of periodontopathic biofilms is a challenge even for AMPs. Thus, the present study evaluates in vitro antimicrobial activity of synthetic peptide LyeTxI and association compound LyeTxI/β-cyclodextrin (βCD) against multispecies biofilms. Sensibility to LyeTxI and LyeTxI/βCD was determined for planktonic Gram-negative periodontopathogens. Time-kill kinetic assay was performed at minimum inhibitory concentrations (MICs) in all planktonic strains. Multispecies biofilms were grown on pegs using a biofilm device and studied by scanning electron microscopy at 2, 5, and 10 days. Minimal biofilm eradication concentration (MBEC) was determined for 2- and 4-day multispecies biofilms. Metabolic activity of biofilms was determined by fluorometry study. Biofilms showed reproducible cell density on pegs of the biofilm device. LyeTxI and LyeTxI/βCD were active against all strains tested at concentrations ≤62.5 μg/mL. Kinetic assays showed rapid bactericidal effect of LyeTxI against all periodontopathogens. MBECs of LyeTxI and LyeTxI/βCD against multispecies 2-day biofilms were two-fold higher than MICs of cells shed from biofilms. LyeTxI was able to reduce multispecies 2-day metabolic activity by 90%. Multispecies 4-day biofilms were tolerant to all agents tested. LyeTxI and LyeTxI/βCD are active against periodontopathic bacteria, showing rapid bactericidal effect and may be used to prevent biofilm development. In the future, AMPs could be therapeutic tools for treatment of periodontitis.

Effective antimicrobial activity of a peptide mutant Cbf-14-2 against penicillin-resistant bacteria based on its unnatural amino acids

Broad spectrum activities, a unique mode of actions and rare resistant variants make antimicrobial peptide (AMP) a potential alternative to antibiotics. However, AMPs still have limitations in clinical development due to their physiological stability, toxicity and manufacturing costs. Cbf-14, derived from cathelicidin-BF has been proven to be effective against drug-resistant bacteria. Herein, a series of Cbf-14 mutants were designed to overcome these limitations. Design strategies included substitutions of lysine (Lys) or leucine (Leu) with similar residues such as ornithine (Orn) and norleucine (Ile), which are unnatural amino acids, to generate AMPs with enhanced therapeutic potential. Antimicrobial activity, hemolytic activity and cytotoxicity against mouse spleen cells of the peptide mutants were investigated. Among all of the mutants, Cbf-14-2 was regarded as the most potent candidate with the amino acid sequence of RLLR-Orn-FFR-Orn-LKKSV-NH2, which exhibited a superior antimicrobial activity with a minimum inhibitory concentration (MIC) of 4–32μg/ml. Meanwhile, Cbf-14-2 displayed low levels of hemolysis in sheep red blood cells (sRBCs) and negligible cytotoxicity against mouse spleen cells, suggesting low toxicity against mammalian cells. A circular dichroism (CD) study indicated that Cbf-14-2 has a higher alpha-helix content than Cbf-14 (68.3% vs 35.1%) in SDS, which may contribute to its superior activity. Time-killing curves showed Cbf-14-2 can eliminate all tested bacteria within 240min, suggesting its rapid bactericidal effect. Transmission electron microscopy (TEM), flow cytometry and calcein release assays revealed its excellent antimicrobial potency by inducing membrane permeation and disruption. In addition, Cbf-14-2 (10mg/kg) could significantly elevate the survival rate of clinical strain infected mice, with a survival rate of 70.0%. Taken together, the data suggest that Cbf-14-2 possesses effective antimicrobial activity against penicillin-resistant bacteria in vitro and in vitro, thus rendering it as a potential anti-infective agent in clinical settings.

Clinical features and treatment of patients with Vibrio vulnificus infection

Infections with Vibrio vulnificus are commonly fatal, and the speed and accuracy of diagnosis and treatment is directly linked to mortality. The main aims of this study were to investigate the clinical characteristics of six patients with V. vulnificus infections retrospectively and to determine the effect of treatment with tigecycline (TGC) alone compared with doxycycline plus ceftazidime (DOX/CAZ). The medical records of patients were reviewed. The species-specific and pathogenic gene markers were detected by PCR, and multilocus sequence typing (MLST) was performed. Furthermore, the effects of TGC and of DOX/CAZ were determined using time-kill assays. MLST revealed six different sequence types and five of them were novel. The complete clinical pattern (vcg type C, CPS operon allele 1, 16S-rRNA type B) was found in one strain and the others had a mixed pattern. The lesion was mainly located at the distal end of the extremities and the most common clinical symptoms were fever, pain, erythema, and local swelling. The in vitro time-kill assay indicated that TGC monotherapy at a concentration of 0.1mg/l had a rapid bactericidal effect against the six tested V. vulnificus strains at 24h. TGC alone might be a better potential therapeutic option than the traditional combination of DOX/CAZ against V. vulnificus.

Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci.

The emergence of antibiotic-resistant bacterial species, such as vancomycin-resistant enterococci (VRE), necessitates the development of new antimicrobials. Here, we investigate the spectrum of antibacterial activity of three phenylthiazole-substituted aminoguanidines. These compounds possess potent activity against VRE, inhibiting growth of clinical isolates at concentrations as low as 0.5 μg/mL. The compounds exerted a rapid bactericidal effect, targeting cell wall synthesis. Transposon mutagenesis suggested three possible targets: YubA, YubB (undecaprenyl diphosphate phosphatase (UPPP)), and YubD. Both UPPP as well as undecaprenyl diphosphate synthase were inhibited by compound 1. YubA and YubD are annotated as transporters and may also be targets because 1 collapsed the proton motive force in membrane vesicles. Using Caenorhabditis elegans, we demonstrate that two compounds (1, 3, at 20 μg/mL) retain potent activity in vivo, significantly reducing the burden of VRE in infected worms. Taken altogether, the results indicate that compounds 1 and 3 warrant further investigation as novel antibacterial agents against drug-resistant enterococci.

Symmetrically Substituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistance with Enhanced Membrane Selectivity.

This is the first report of the design of a new series of symmetric xanthone derivatives that mimic antimicrobial peptides using a total synthesis approach. This novel design is advantageous because of its low cost, synthetic simplicity and versatility, and easy tuning of amphiphilicity by controlling the incorporated cationic and hydrophobic moieties. Two water-soluble optimized compounds, 6 and 18, showed potent activities against Gram-positive bacteria, including MRSA and VRE (MICs = 0.78-6.25 μg/mL) with a rapid bactericidal effect, low toxicity, and no emergence of drug resistance. Both compounds demonstrated enhanced membrane selectivity that was higher than those of most membrane-active antimicrobials in clinical trials or previous reports. The compounds appear to kill bacteria by disrupting their membranes. Significantly, 6 was effective in vivo using a mouse model of corneal infection. These results provide compelling evidence that these compounds have therapeutic potential as novel antimicrobials for multidrug-resistant Gram-positive infections.