New Types Of Antibiotics Research Articles

Antibacterial activity of Balinese Traditional Herbs Elephantopus Scaber Linn and Curcuma aeruginosa Roxb against Burkholderia pseudomallei, Staphylococcus aureus, and Salmonella typhimurium

Background: Herbal medicinal plants are considered one of the sources for new types of antibiotics due to their secondary metabolite that may have antibacterial effects. Tapak Liman (Elephantopus scaber linn) and Temu Ireng (Curcuma aeruginosa roxb) are two medicinal plants that have potential as antibacterial agents due to their secondary metabolite contents. This study aimed to investigate the secondary metabolite contents of tapak liman and temu ireng grown locally in Bali and their antibacterial activity against Burkholderia pseudomallei, Staphylococcus aureus, and Salmonella typhimurium. Methods: This post-test experimental research was conducted from June to December 2021 at the Universitas Warmadewa Faculty of Medicine and Health Sciences Research Laboratory. Tapak liman leaves and temu ireng rhizomes, sourced from a local garden in Denpasar, Bali, were used. Ethanolic extracts of these plants were tested for secondary metabolites and their antibacterial activity against Staphylococcus aureus, Salmonella typhimurium, and Burkholderia pseudomallei. Results: A phytochemical analysis of tapak liman from Denpasar shows that it contains alkaloids and phenols, while temuireng contains flavonoids, tannins, and phenols. Antibacterial tests revealed that both plants have a weak effect against gram-positive Staphylococcus aureus but negligible effect against gram-negative Burkholderia pseudomallei and Salmonella typhimurium. Conclusion: Both tapak liman and temu ireng ethanolic extract have weak antibacterial properties against gram-positive Staphylococcus aureus and negligible/no antibacterial properties against gram-negative Burkholderia pseudomallei and Salmonella typhimurium.

Cationic Porphyrins as Antimicrobial and Antiviral Agents in Photodynamic Therapy.

Antimicrobial photodynamic therapy (APDT) has received a great deal of attention due to its unique ability to kill all currently known classes of microorganisms. To date, infectious diseases caused by bacteria and viruses are one of the main sources of high mortality, mass epidemics and global pandemics among humans. Every year, the emergence of three to four previously unknown species of viruses dangerous to humans is recorded, totaling more than 2/3 of all newly discovered human pathogens. The emergence of bacteria with multidrug resistance leads to the rapid obsolescence of antibiotics and the need to create new types of antibiotics. From this point of view, photodynamic inactivation of viruses and bacteria is of particular interest. This review summarizes the most relevant mechanisms of antiviral and antibacterial action of APDT, molecular targets and correlation between the structure of cationic porphyrins and their photodynamic activity.

New Teixobactin Analogues with a Total Lactam Ring.

Teixobactin is a new antibiotic peptide with strong efficacy against several Gram-positive resistant bacteria, the structure of which is extremely difficult to obtain in the laboratory via multistep conventional synthesis. To face the increasing antibiotic resistant bacteria, it is fundamental to introduce new types of antibiotics with innovative mechanisms of action without resistance; thus, many scientists are studying and developing new methods to synthesize teixobactin analogues. In this work, seven Arg10-teixobactin analogues with a total lactam ring have been prepared via solid phase peptide synthesis. In order to obtain the total lactam ring, d-Thr8 was replaced by (2R,3S)-diamino-propionic acid. To verify their antimicrobial activity and efficacy, each analogue was tested with MIC against different resistant pathogens, showing an interesting activity for Nle11 containing compounds.

The inhibitory activity of a new scorpion venom-derived antimicrobial peptide Hp1470 against Gram-positive bacteria

Antimicrobial peptides (AMPs) are a new type of antibiotic and target a variety of microbes, including antibiotic-resistant strains; thus, AMPs have attracted widespread interest. Scorpion venoms contain many bioactive peptides, including AMPs, and have become an important natural resource of peptide-based drugs. Here, the antibacterial peptide gene Hp1470 from the venom of the scorpion Heterometrus petersii was characterized, and its antibacterial activity was determined. The cDNA sequence of Hp1470 is 300 nt in length and contains an open reading frame (ORF) of 207 nt. The ORF was shown to encode 68 amino acid residues, including a signal peptide (23 aa), a mature peptide (13 aa), a C-terminal posttranslational processing signal (3 aa), and a propeptide (29 aa). Multiple sequence alignment results indicated that Hp1470 is an antibacterial peptide. The mature peptide Hp1470, which has a molecular mass of 1564.09 Da, was further chemically synthesized with a purity of greater than 95%. Antimicrobial assays showed that the synthesized Hp1470 exerted an inhibitory effect on Gram-positive bacteria and clinical drug-resistant strains, including PRSA and MRSA, but not Gram-negative bacteria. Hp1470 was further found to protect mice from MRSA infection, suggesting its potential application as an in vivo antimicrobial agent. Interestingly, Hp1470 only inhibited bacterial growth but did not kill bacteria, which was consistent with scanning electron microscopy results showing that Hp1470 did not lyse the cell membrane of Staphylococcus aureus. Our work provides a new direction for developing antibacterial agents with different modes of action from natural scorpion venoms.

Revealing the single-channel characteristics of OprD (OccAB1) porins from hospital strains of Acinetobacter baumannii.

Nowadays, reports of antimicrobial resistance (AMR) against many antibiotics are increasing because of their misapplication. With this rise, there is a serious decrease in the discovery and development of new types of antibiotics amid an increase in multi-drug resistance. Unfermented Acinetobacter baumannii from gram-negative bacteria, which is one of the main causes of nosocomial infections and multi-drug resistance, has 4 main kinds of antibiotic resistance mechanism: inactivating antibiotics by enzymes, reduced numbers of porins and changing of their target or cellular functions due to mutations, and efflux pumps. In this study, characterization of the possible mutations in OprD (OccAB1) porins from hospital strains of A. baumannii were investigated using single channel electrophysiology and compared with the standard OprD isolated from wild type ATCC 19,606. For this aim, 5 A. baumannii bacteria samples were obtained from patients infected with A. baumannii, after which OprD porins were isolated from these A. baumannii strains. OprD porins were then inserted in an artificial lipid bilayer and the current-voltage curves were obtained using electrical recordings through a pair of Ag/AgCl electrodes. We observed that each porin has a characteristic conductance and single channel recording, which then leads to differences in channel diameter. Finally, the single channel data have been compared with the gene sequences of each porin. It was interesting to find out that each porin isolated has a unique porin diameter and decreased anion selectivity compared to the wild type.

In silico optimization of RNA–protein interactions for CRISPR-Cas13-based antimicrobials

RNA–protein interactions are crucial for diverse biological processes. In prokaryotes, RNA–protein interactions enable adaptive immunity through CRISPR-Cas systems. These defence systems utilize CRISPR RNA (crRNA) templates acquired from past infections to destroy foreign genetic elements through crRNA-mediated nuclease activities of Cas proteins. Thanks to the programmability and specificity of CRISPR-Cas systems, CRISPR-based antimicrobials have the potential to be repurposed as new types of antibiotics. Unlike traditional antibiotics, these CRISPR-based antimicrobials can be designed to target specific bacteria and minimize detrimental effects on the human microbiome during antibacterial therapy. In this study, we explore the potential of CRISPR-based antimicrobials by optimizing the RNA–protein interactions of crRNAs and Cas13 proteins. CRISPR-Cas13 systems are unique as they degrade specific foreign RNAs using the crRNA template, which leads to non-specific RNase activities and cell cycle arrest. We show that a high proportion of the Cas13 systems have no colocalized CRISPR arrays, and the lack of direct association between crRNAs and Cas proteins may result in suboptimal RNA–protein interactions in the current tools. Here, we investigate the RNA–protein interactions of the Cas13-based systems by curating the validation dataset of Cas13 protein and CRISPR repeat pairs that are experimentally validated to interact, and the candidate dataset of CRISPR repeats that reside on the same genome as the currently known Cas13 proteins. To find optimal CRISPR-Cas13 interactions, we first validate the 3-D structure prediction of crRNAs based on their experimental structures. Next, we test a number of RNA–protein interaction programs to optimize the in silico docking of crRNAs with the Cas13 proteins. From this optimized pipeline, we find a number of candidate crRNAs that have comparable or better in silico docking with the Cas13 proteins of the current tools. This study fully automatizes the in silico optimization of RNA–protein interactions as an efficient preliminary step for designing effective CRISPR-Cas13-based antimicrobials.

Defects in DNA double-strand break repair resensitize antibiotic-resistant Escherichia colito multiple bactericidal antibiotics.

Antibiotic resistance is becoming increasingly prevalent amongst bacterial pathogens and there is an urgent need to develop new types of antibiotics with novel modes of action. One promising strategy is to develop resistance‐breaker compounds, which inhibit resistance mechanisms and thus resensitize bacteria to existing antibiotics. In the current study, we identify bacterial DNA double‐strand break repair as a promising target for the development of resistance‐breaking co‐therapies. We examined genetic variants of Escherichia coli that combined antibiotic‐resistance determinants with DNA repair defects. We observed that defects in the double‐strand break repair pathway led to significant resensitization toward five bactericidal antibiotics representing different functional classes. Effects ranged from partial to full resensitization. For ciprofloxacin and nitrofurantoin, sensitization manifested as a reduction in the minimum inhibitory concentration. For kanamycin and trimethoprim, sensitivity manifested through increased rates of killing at high antibiotic concentrations. For ampicillin, repair defects dramatically reduced antibiotic tolerance. Ciprofloxacin, nitrofurantoin, and trimethoprim induce the promutagenic SOS response. Disruption of double‐strand break repair strongly dampened the induction of SOS by these antibiotics. Our findings suggest that if break‐repair inhibitors can be developed they could resensitize antibiotic‐resistant bacteria to multiple classes of existing antibiotics and may suppress the development of de novo antibiotic‐resistance mutations.

In-vitro and in-silico antibacterial activity of Azadirachta indica (Neem), methanolic extract, and identification of Beta.d-Mannofuranoside as a promising antibacterial agent

BackgroundAntimicrobial resistance became the leading cause of death globally, resulting in an urgent need for the discovery of new, safe, and efficient antibacterial agents. Compounds derived from plants can provide an essential source of new types of antibiotics. A. indica (neem) plant is rich in antimicrobial phytoconstituents. Here, we used the sensitive and reliable gas chromatography-mass spectrometry (GC–MS) approach, for the quantitative and quantitative determination of bioactive constituents in methanolic extract of neem leaves grown in Sudan. Subsequently, antibacterial activity, pharmacokinetic and toxicological properties were utilized using in silico tools.ResultsThe methanolic extract of neem leaves was found to have antibacterial activity against all pathogenic and reference strains. The lowest concentration reported with bacterial activity was 3.125%, which showed zones of inhibition of more than 10 mm on P. aeruginosa, K. pneumoniae, Citrobacter spp., and E. coli, and 8 mm on Proteus spp., E. faecalis, S. epidermidis, and the pathogenic S. aureus. GC–MS analysis revealed the presence of 30 chemical compounds, including fatty acids (11), hydrocarbons (9), pyridine derivatives (2), aldehydes (2), phenol group (1), aromatic substances (1), coumarins (1), and monoterpenes (1). In silico and in vitro tools revealed that.beta.d-Mannofuranoside, O-geranyl was the most active compound on different bacterial proteins. It showed the best docking energy (-8 kcal/mol) and best stability with different bacterial essential proteins during molecular dynamic (MD) simulation. It also had a good minimum inhibitory concentration (MIC) (32 μg/ml and 64 μg/ml) against S. aureus (ATCC 25,923) and E. coli (ATCC 25,922) respectively.ConclusionThe methanolic extract of A. indica leaves possessed strong antibacterial activity against different types of bacteria. Beta.d-Mannofuranoside, O-geranyl was the most active compound and it passed 5 rules of drug-likeness properties. It could therefore be further processed for animal testing and clinical trials for its possible use as an antibacterial agent with commercial values.

Evaluation of a new antimicrobial agent production (RSMM C3) by using metagenomics approaches from Egyptian marine biota

Diseases and epidemics in the current days need new types of antibiotics in order to be able to eliminate them. The goal of this research is to use metagenomics to identify isolated utilitarian gene (s) as antimicrobial specialists. Collection of diverse locations from sea sediment samples from Alexandria and extraction of total DNA, restriction enzyme fragmentation, cloning into pUC19 vector, and expression of the isolated gene(s) in E. coli DH5α were all part of the process. Characterization of Antimicrobial agent was done for the best clone for antimicrobial agent's production to detect efficiency, optimum pH, thermal stability, pH stability, effect of different compounds on antimicrobial activity, and residual activity of product after preservation in room temperature. Amino acid sequence of RSMM C3 gene (1250 bp) was 72% identity with Herbaspirillum sp. The ideal temperature level of the RSMM C3 antimicrobial agent production was 36 °C. The antimicrobial agent RSMM C3′s stability was stable at -20 °Celsius for up to two months without thawing. The antibacterial agent RSMM C3 was stable at 4 °C for 14 days without loss in activity. The ideal pH level of the RSMM C3 antimicrobial agent was 6. Remain activity was gradually decreased at pH 5, 6, 6.5 and 7 (86.1, 96.9, 97.2 and 94.9%, respectively). On the other hand, residual activity was (92 and 84%) at (pH 7.5 and 8) for 8 days. The tested antimicrobial RSMM C3 was stable against 1 mM of different compounds (DMSO, Glycerol, NaCl, CaCl2, MgCl2, ZnCl2, FeSO4, MnSO4 and CuSO4). The research provides for the Metagenomics technique that has the ability for the production of novel antimicrobial agents produced by clone RSMM C3 which has a wide spectrum activity towards different microorganisms comparing to other antibiotics as Ampicillin and Tetracycline.

Potensi Metabolit Sekunder Isolat Aktinomycetes Sebagai Penghasil Senyawa Antibakteri Terhadap Methicillin Resistant Staphylococcus aureus (MRSA) Dari Tanah Mangrove Wonorejo Surabaya

Infectious diseases are estimated to be the cause of half of all deaths worldwide. About 50-75% of deaths in hospital are reported to be due to infection. This number continues to increase rapidly in line with the development of bacterial resistance to certain antibiotics. One of the causes of resistance due to antibiotic abuse. The number of resistance events that occur encourages new discoveries in order to overcome the problem of resistance. Actinomycetes are Gram-positive microscopic bacteria that are widespread in nature. These bacteria can live in various environmental conditions that contain lots of nutrients. Actinomycetes population increases in the presence of organic matter that undergoes decomposition. Acinomycetes have the ability to produce antimicrobial compounds. The need for antibiotic compounds and chemotherapy compounds that are effective with low toxicity to the host, and the resulting waste can be degraded by the environment, is a problem that needs serious attention. The existence of resistance to antibiotics causes the need to develop new types of antibiotics from natural ingredients and microorganisms that can control microbapatogens. Compounds obtained from natural materials, especially plants and microbes, provide promising results in the development of new antibiotic compounds, among the existing types of microorganisms, Actinomycetes are the most potential source of producing antibiotics. Apart from antibiotics, actinomycetes also produce bioactive compounds of high economic value in the health sector as antiviral and anti-cancer, while in agriculture as herbicides, insecticides, and anti-parasitic compounds. This causes the need to explore actinomycetes which have the potential to produce antibiotic compounds against bacteria. This study aims to determine the antibacterial activity of secondary metabolites of actinomycetes isolates against cuts infected with Staphylococcus aureus resistant methicillin (MRSA) in winstar rats (rattus norvegicus). This type of research is carried out in an experimental laboratory. The results showed that the potential for secondary metabolites of actinomysetes isolates against MRSA bacteria was classified as strong with an inhibitory index of 10.1.

One Health strategy to prevent and control antibiotic resistance

Antibiotic resistance affects the development of the world economy and threats public health. China is one of the countries with the most severe abuse of antibiotics. Here, we describe the causes of antibiotic resistance in the environment, human and animals as well as the status of antibiotic resistance. Based on the concept of One Health, we propose the promotion of the scientific use of antibiotics, the development of new types of antibiotics, establishment of the antibiotics stereoscopic monitoring network system, the promotion of knowledge education of antibiotic resistance, prevention of infection and other measures. We call for the establishment of interdisciplinary, cross-sectoral, trans-regional communication and cooperation to promote the development of antibiotic resistance prevention and control in China to protect environment and the health of humans and animals.

Design and examination of potent pseudosubstrate-based oligonucleotide inhibitors against bacterial topoisomerase IV

Topoisomerase IV is an enzyme that is mainly responsible for unwinding interlocked DNA strands at the final stage of prokaryotic DNA replication. Due to its exclusivity in prokaryotes, topoisomerase IV has been identified as a validated target for quinolone-based antibiotics in the past years for treating bacterial infection. In consideration that bacterial resistance to such antibiotics has occurred constantly, several newly designed pseudosubstrate oligonucleotides as DNA topoisomerase IV inhibitors have been examined during our recent investigations. Among them, the nick-, gap- and mismatched base pair-containing oligonucleotides displayed significantly high inhibitory effects toward topoisomerase IV. It is our anticipation that the outcomes of our current studies could be beneficial for the future development of pseudosubstrate-based enzyme inhibitors as well as new types of antibiotics.

Discovery of Phylloseptins that Defense against Gram-Positive Bacteria and Inhibit the Proliferation of the Non-Small Cell Lung Cancer Cell Line, from the Skin Secretions of Phyllomedusa Frogs.

The growing occurrence of bacterial resistance to conventional antibiotics has called for the development of new classes of antimicrobial agents. Antimicrobial peptides (AMPs) with broad antimicrobial spectrum derived from frog skin secretions have been demonstrated to be promising candidates for new antibiotic development. A proven rich source of these compounds are the skin secretions of the frogs in the Phyllomedusa genus. In this study, two novel phylloseptin peptides—phylloseptin-PTa and phylloseptin-PHa—were isolated from the skin secretions of the South American frogs, Phyllomedusa tarsius (P. tarsius) and Phyllomedusa hypochondrialis (P. hypochondrialis) through parallel transcriptomic and peptidomic studies. Replicates obtained by chemical synthesis were structurally analysed and shown to adopt an α-helix configuration in an amphiphilic environment. Both peptides demonstrated antimicrobial activities against planktonic Gram-positive bacteria strains, including Staphylococcus aureus, Enterococcus faecalis and methicillin-resistant Staphylococcus aureus , biofilms, as well as cytostatic effects on the non-small cell lung cancer cell line, NCI-H157, with relatively low haemolysis on horse erythrocytes and low cytotoxicity on the human microvascular endothelial cell line, HMEC-1. The discovery of phylloseptin peptides may further inspire the development of new types of antibiotics.

Design and surface immobilization of short anti-biofilm peptides.

It is stunning that the total deaths due to methicillin-resistant Staphylococcus aureus (MRSA) infection are comparable to AIDS/HIV-1, making it urgent to explore new possibilities. This study deals with this problem by two strategies. First, we have designed a family of novel antimicrobial peptides with merely eight amino acids, making it cost effective for chemical synthesis. These peptides are potent against MRSA USA300. Our study uncovers that the high potency of the tryptophan-rich short peptide is coupled with arginines, whereas these Trp- and Arg-rich peptides are less toxic to select human cells than the lysine-containing analogs. Such a combination generates a more selective peptide. As a second strategy, we also demonstrate successful covalent immobilization of this short peptide to the polyethylene terephthalate (PET) surface by first using a chitosan linker, which is easy to obtain. Because biofilms on medical devices are difficult to remove by traditional antibiotics, we also show that the peptide coated surface can prevent biofilm formation. Although rarely demonstrated, we provide evidence that both the free and immobilized peptides target bacterial membranes, rendering it difficult for bacteria to develop resistance. Collectively, the significance of our study is the design of novel antimicrobial peptides provides a useful template for developing novel antimicrobials against MRSA. In addition, orientation-specific immobilization of the same short peptide can prevent biofilm formation on the PET surface, which is widely used in making prosthetic heart valves cuffs and other bio devices.

Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections.

Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell–cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy.

Mechanisms of Pyrazinamide Action and Resistance.

PZA is a unique anti-tuberculosis drug that plays a key role in shortening the TB therapy. PZA kills non-replicating persisters that other TB drugs fail to kill, and thus making it an essential drug for inclusion in any drug combinations for treating drug susceptible and drug-resistant TB such as MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation and perhaps pantothenate /coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase involved in conversion of the prodrug PZA to the active form POA. Mutations in the drug target RpsA are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype based PZA susceptibility testing is not reliable due to false resistance, and sequencing of the pncA gene represents a more rapid, cost-effective and more reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a 'tipping point' that inspires new efforts at developing a new type of antibiotics or drugs that target non-replicating persisters for improved treatment of not only TB but also other persistent bacterial infections.

Characterization of antibacterial and hemolytic activity of synthetic pandinin 2 variants and their inhibition against Mycobacterium tuberculosis.

The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects.

The gallium(III)–salicylidene acylhydrazide complex shows synergistic anti-biofilm effect and inhibits toxin production by Pseudomonas aeruginosa

Bacterial biofilms cause a range of problems in many areas and especially in health care. Biofilms are difficult to eradicate with traditional antibiotics and consequently there is a need for alternative ways to prevent and/or remove bacterial biofilms. Furthermore, the emergence of antibiotic resistance in bacteria creates a challenge to find new types of antibiotics with a lower evolutionary pressure for resistance development. One route to develop such drugs is to target the so called virulence factors, i.e. bacterial systems used when bacteria infect a host cell. This study investigates synergy effects between Ga(III) ions, previously reported to suppress biofilm formation and growth in bacteria, and salicylidene acylhydrazides (hydrazones) that have been proposed as antivirulence drugs targeting the type three secretion system used by several Gram-negative pathogens, including Pseudomonas aerugionosa, during bacterial infection of host cells. A library of hydrazones was screened for: Fe(III) binding, enhanced anti-biofilm effect with Ga(III) on P. aeruginosa, and low cytotoxicity to mammalian cells. The metal coordination for the most promising ligand, 2-Oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (ME0163) with Ga(III) was investigated using extended X-ray absorption fine structure spectroscopy as well as density functional theory. The results showed that Ga(III) chelates the hydrazone with 5- and 6-membered chelating rings, and that the Ga(III)–ME0163 complex enhanced the antibiofilm effect of Ga(III) while suppressing the type three secretion system in P. aeruginosa. The latter effect was not observed for the hydrazone alone and was similar for Ga(III)–citrate and Ga(III)–ME0163 complexes, indicating that the inhibition of virulence was caused by Ga(III).

Biosynthesis of new lipopentapeptides by an engineered strain of Streptomyces sp.

Arylomycins are type I signal peptidase inhibitors and have a potential as a new type of antibiotics. They were identified from the broth of Streptomyces sp. HCCB10043. The arylomycin biosynthetic gene cluster in this strain was identical to that in S. roseosporus. Within the gene cluster, aryC, encoding a P450 enzyme, was deduced to be responsible for biaryl bond formation in, the arylomycins. Inactivation of aryC abolished arylomycin production and led to the generation of two novel linear lipopentapeptides lacking the aryl-aryl linkage. These derivatives had lost their antibacterial activities against Staphylococcus epidermidis which is sensitive to arylomycins A2 and A4.

Antimicrobial activity of ruthenium-based intercalators

Multidrug resistance of bacterial pathogens is a major problem and there is a clear need for the development of new types of antibiotics. Here we investigated the antimicrobial activity of ruthenium(II) based DNA-intercalating complexes. These complexes were found to have no activity in vitro against the Gram-negative bacterium Escherichia coli, but the complexes were clearly active against the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. In vivo activity has also been demonstrated for one of the compounds using a simple infection model, the nematode Caenorhabditis elegans. Importantly, this also showed that the compound tested was not toxic to the nematodes.