Source Of New Antibiotics Research Articles

Global analysis of biosynthetic gene clusters reveals vast potential of secondary metabolite production in Penicillium species.

Filamentous fungi produce a wide range of bioactive compounds with important pharmaceutical applications, such as antibiotic penicillins and cholesterol-lowering statins. However, less attention has been paid to fungal secondary metabolites compared to those from bacteria. In this study, we sequenced the genomes of 9 Penicillium species and, together with 15 published genomes, we investigated the secondary metabolism of Penicillium and identified an immense, unexploited potential for producing secondary metabolites by this genus. A total of 1,317 putative biosynthetic gene clusters (BGCs) were identified, and polyketide synthase and non-ribosomal peptide synthetase based BGCs were grouped into gene cluster families and mapped to known pathways. The grouping of BGCs allowed us to study the evolutionary trajectory of pathways based on 6-methylsalicylic acid (6-MSA) synthases. Finally, we cross-referenced the predicted pathways with published data on the production of secondary metabolites and experimentally validated the production of antibiotic yanuthones in Penicillia and identified a previously undescribed compound from the yanuthone pathway. This study is the first genus-wide analysis of the genomic diversity of Penicillia and highlights the potential of these species as a source of new antibiotics and other pharmaceuticals.

YENİ BİR DOĞAL ANTİBİYOTİK: “TEİKSOBAKTİN”

Antibiotic resistance is spreading faster than the introduction of new antimicrobials into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms. This limited resource of cultivable bacteria was overmined by the 1960s. It is reported that uncultured bacteria by in vitro conditions make up approximately 99% of all species in external environments, and are a source of new antibiotics which could not be explored yet. The new technology for growing uncultured organisms by cultivation in situ or by using specific growth factors have been developed. As a result, it is reported that a new antibiotic termed as teixobactin has been discovered in the screening of the new soil bacterium named as Eleftheria terrae. Teixobactin has bactericidal effects in Grampositive bacteria inhibiting cell wall synthesis by binding to lipid II which is a a highly conserved precursor of peptidoglycan and lipid III which is a precursor of cell wall teichoic acid. It has been tested in two animal infection models: blood infections of methicillin-resistant Staphylococcus aureus and lung infections of Streptococcus pneumoniae. As a result, all animals were treated successfully and none developed resistance. If teixobactin is approved, it will be the first of a new class of antibiotics.

Human commensals producing a novel antibiotic impair pathogen colonization.

The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.

Antimicrobial and Antioxidant Activity of Endophyte Bacteria Associated with Curcuma longa Rhizome

Most cases of bacterial resistance towards antibiotics, encourage various efforts to gain new sources of antibiotics. Endophyte bacteria is a microorganism has important role as the producer of bioactive compounds. Endophyte bacteria from Curcuma longa with antimicrobial and antioxidant activities have not been studied yet. Curcuma longa has been utilized as the main ingredients of traditional herbal medicines ( jamu ). The objective of this research was to investigate the antimicrobial and antioxidant activity of endophyte bacteria associated with Curcuma longa rhizome. Based on morphological characteristics of bacterial colonies, eight endophyte bacteria was isolated from Curcuma longa rhizome. Screening of endophyte isolate has antimicrobial activity was done using agar well diffusion method. The culture supernatant of each endophyte isolate was dropped on agar well against pathogenic bacteria Salmonella enterica ser. Typhi, Staphylococcus aureus and yeast Candida albicans . Three endophyte isolates K 3 , K 2 and M 1b showed antimicrobial activity against pathogenic bacteria and yeast. Isolate K 3 showed strong antimicrobial activity against C. albicans and S. aureus , however, isolate K 2 and isolate M 1b showed antimicrobial activity against S almonella enterica ser. Typhi and S. aureus , respectively. Those endophyte bacteria also had antioxidant activity shown by scavenging ability toward DPPH radical with consecutive percentage of isolate K 3 (72.3 %), K 2 (51.3 %) and M 1b (64.6 %). Isolate K 3 showed the highest antimicrobial and antioxidant activity. Based on biochemical characteristics using Microbact 24E kit, isolate K 3 was identified as Paenibacilus alvei and isolate K 2 as Enterobacter agglomerans . Keywords: antimicrobial, antioxidant, Curcuma longa ’s rhizome, endophyte bacteria.

A TonB-dependent receptor regulates antifungal HSAF biosynthesis in Lysobacter.

Lysobacter species are Gram-negative bacteria that are emerging as new sources of antibiotics, including HSAF (Heat Stable Antifungal Factor), which was identified from L. enzymogenes with a new mode of action. LesR, a LuxR solo, was recently shown to regulate the HSAF biosynthesis via an unidentified mechanism in L. enzymogenes OH11. Here, we used a comparative proteomic approach to identify the LesR targets and found that LesR influenced the expression of 33 proteins belonging to 10 functional groups, with 9 proteins belonging to the TBDR (TonB-Dependent Receptor) family. The fundamental role of bacterial TBDR in nutrient uptake motivates us to explore their potential regulation on HSAF biosynthesis which is also modulated by nutrient condition. Six out of 9 TBDR coding genes were individually in-frame deleted. Phenotypic and gene-expression assays showed that TBDR7, whose level was lower in a strain overexpressing lesR, was involved in regulating HSAF yield. TBDR7 was not involved in the growth, but played a vital role in transcribing the key HSAF biosynthetic gene. Taken together, the current lesR-based proteomic study provides the first report that TBDR7 plays a key role in regulating antibiotic (HSAF) biosynthesis, a function which has never been found for TBDRs in bacteria.

Could Frog Skin Peptides Be Source of New Antibiotics?

Could Frog Skin Peptides Be Source of New Antibiotics?

Teixobactin: A New Antibiotic Without Resistance? Stay Tuned

Although antibiotics have transformed medicine, the development of resistance has limited their usefulness. A potential source of new antibiotics is

A new antibiotic kills pathogens without detectable resistance.

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

Isolation and Evaluation of Antimicrobial Activities of Endophytic Fungal Extract from Mallotus philippinensis Muell

Mallotus philippinensis Muell an important medicinal plant in the present study i.e., endophytic extracts of different fungi associated with asymptomatic were evaluated for antimicrobial activity. This will be a new promising source of antimicrobials known as endophytes. In this preliminary study, different parts of plants viz. steam and leaves were used for isolation of endophytic fungi and fermented. The endophytic fungi were identified based on their morphology and characteristics of fungal spores. The cell free ferment broth was subjected to antimicrobial assay against different human pathogenic microbes viz. Escherichia coli, Staphylococcus aureus, E. faecalis, K .pneumoniae and P. aeruginosa and three fungal pathogenic strains of candida i.e. C. albicans, C. tropicalis and C. krusie by using standard disc diffusion method. The results showed that some of these endophytic extracts had prominent antimicrobial inhibitory effects. Among these fungal endophytes, two strains Alternaria spp., Pestalotiopsis spp., and Phompsis spp. showed the strongest antimicrobial activities against P. aeruginosa, S. aureus and E. faecalis. An endophyte Pestalotiopsis spp. had the most pronounced effect on all the Candida strains exhibited the strongest antifungal activity. This present study has proven that both these medicinal plants may be a rich source of endophytic fungi with potential to produce bioactive producing antibacterial and antifungal activities. These antipathogenic endophytes could be applied as new sources of antibiotics in agriculture and pharmaceutical industry.

Investigatory Study on Antimicrobial Activity and Phytochemical Screening of Butea monosperma Linn

Infectious diseases are the second leading cause for worldwide death. Treatment of infections continues to be problematic in modern time because of the severe side effects of some drugs and the growing resistance to antimicrobial agents. Over the past few decades the use of antibiotics is under threat as many commonly used antibiotics have become less effective against certain illnesses due to emergence of multi drug-resistant (MDR) bacteria. The continuous search for the source of new antibiotics is needed to face the problem of increasing resistant strains of bacteria. It is known that more than 400,000 species of tropical flowering plants possesses medicinal properties through their phytochemical constituents. Considering the important role of Butea monosperma in inhibition of different cultures of bacteria, the present study was conducted to evaluate its antimicrobial spectrum against different life threatening pathogenic microorganisms and screening for various phytochemical constituents.

Identification of a small molecule signaling factor that regulates the biosynthesis of the antifungal polycyclic tetramate macrolactam HSAF in Lysobacter enzymogenes.

Lysobacter species are emerging as new sources of antibiotics. The regulation of these antibiotics is not well understood. Here, we identified a small molecule metabolite (LeDSF3) that regulates the biosynthesis of the antifungal antibiotic heat-stable antifungal factor (HSAF), a polycyclic tetramate macrolactam with a structure and mode of action distinct from the existing antifungal drugs. LeDSF3 was isolated from the culture broth of Lysobacter enzymogenes, and its chemical structure was established by NMR and MS. The purified compound induced green fluorescence in a reporter strain of Xanthomonas campestris, which contained a gfp gene under the control of a diffusible signaling factor (DSF)-inducible promoter. Exogenous addition of LeDSF3 in L. enzymogenes cultures significantly increased the HSAF yield, the transcription of HSAF biosynthetic genes, and the antifungal activity of the organism. The LeDSF3-regulated HSAF production is dependent on the two-component regulatory system RpfC/RpfG. Moreover, LeDSF3 upregulated the expression of the global regulator cAMP receptor-like protein (Clp). The disruption of clp led to no HSAF production. Together, the results show that LeDSF3 is a fatty acid-derived, diffusible signaling factor positively regulating HSAF biosynthesis and that the signaling is mediated by the RfpC/RpfG-Clp pathway. These findings may facilitate the antibiotic production through applied genetics and molecular biotechnology in Lysobacter, a group of ubiquitous yet underexplored microorganisms.

The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs

Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07μM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4μg/mL, representing a significant improvement in antitubercular potency in this class of compounds.

Lantibiotics: Promising candidates for future applications in health care

The immense potential of bacteria for production of antimicrobials represents an inexhaustible source of new antibiotics. An emerging class of natural products is constituted by ribosomally synthesized and posttranslationally modified peptides (RiPPs). “Lantibiotics” (lanthionine and/or methyl-lanthionine containing antibiotics) belong to the earliest members of this class. The characteristic thioether amino acids are introduced into the precursor peptides by enzyme-mediated posttranslational modifications. The encouraging antimicrobial activity of lantibiotics against multiresistant clinical pathogens, their stability against proteases, heat and oxidation make lantibiotics interesting candidates for novel antimicrobial applications in many areas of the healthcare sector and associated industries. In addition to applications as alternatives to classical antibiotics, lantibiotics can be used as probiotics, prophylactics or additives. Furthermore, the in vitro activity of the lantibiotic modification machinery opens the possibility to generate either improved synthetic lantibiotic peptides or to introduce thioether cross-links into existing therapeutics.

Isolation and partial characterization of cyclic lipopeptide antibiotics produced by Paenibacillus ehimensis B7

BackgroundThe prevalence of drug-resistant bacteria has encouraged the search for novel antimicrobial compounds. Food-associated microorganisms, as a source of new antibiotics, have recently received considerable attention. The objective of this study was to find novel antimicrobial agents produced by food microorganisms.ResultsA bacterial strain B7, which has potent antimicrobial activity, was isolated from a sample of dairy waste. This strain was identified as Paenibacillus ehimensis based on the 16S rRNA gene sequence analysis, physiological and biochemical characterization. Two active compounds (PE1 and PE2) were obtained from P. ehimensis B7. Mass spectrometry (MS) analysis showed that the molecular masses of PE1 and PE2 were 1,114 and 1,100 Da, respectively. The tandem MS and amino acid analysis indicated that PE1 and PE2 were analogs of polypeptin, and PE2 was characterized as a new member of this family. Both compounds were active against all tested bacterial pathogens, including methicillin resistant Staphylococcus aureus, Escherichia coli, and pan-drug resistant Pseudomonas aeruginosa clinical isolate. Time-kill assays demonstrated that at 4 × MIC (minimum inhibitory concentration), PE1 and PE2 rapidly reduced the number of viable cells by at least 3-orders of magnitude, indicating that they were bactericidal antibiotics.ConclusionsIn the present work, two cationic lipopeptide antibiotics (PE1 and PE2) were isolated from P. ehimensis B7 and characterized. These two peptides showed broad antimicrobial activity against all tested human pathogens and are worthy of further study.

Evaluation of antimicrobial activities of extracts of endophytic fungi from <i>Artemisia annua</i>

The endophytic extracts of 11 fungi associated with asympomatic Artemisia annua Linn., were evaluated for antimicrobial activity against three human pathogenic microbes, Escherichia coli, Staphylococcus aureus and Trichophyton rubrum, and two plant pathogens, Rhizoctonia cerealis and Magnaporthe grisea. The results showed that these endophytic extracts had different inhibitory effects on microbial pathogens at 100 mg/mL. Among these fungal endophytes, three strains Aspergillus spp. SPS-02, SPS-04 and SPS-01 respectively showed the strongest antimicrobial activities against E. coli, S. aureu, T. rubrum. An endophytic Mucor sp. SPS-11 had the most pronounced effect on R. cerealis. Two strains Aspergillus sp. SPS-02 and Cephalosporium sp. SPS-08 exhibited the strongest antimicrobial activities against M. grisea. These anti-pathogenic endophytes could be applied as new sources of antibiotics in agriculture and pharmaceutical industry.

Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity suggesting it plays an important role in antibiotic function.

Antimicrobial resistance in the age of noncommunicable diseases.

The opportunity to address the 51st PAHO Directing Council is a great privilege and one that I approach with considerable humility and hesitancy. Like many of you, last week I was in New York City at the historic United Nations General Assembly Special Session on Non-Communicable Diseases or NCDs. We heard that NCDs were a socioeconomic challenge of “epidemic proportions” that kills about 36 million people a year, mostly in low- and middle-income countries. The Secretary-General characterized the situation as “grim” and “one of the major challenges for development in the twenty-first century.” Against the historic trumpet call to global action on NCDs, it might seem that my task today is a bit off key; perhaps I am even singing the wrong song. Has the timeliness of a PAHO Directing Council session on antimicrobial resistance been overcome by events? How do we blend the notes that were sung so loudly in New York last week with our task today to address antimicrobial resistance?First, it is useful to recognize that the conse-quences of NCDs often include infections. Indeed, it will be a very long time before we no longer need to worry about diabetic skin infections, pneumonias complicating chronic lung disease, and opportunistic infections that arise as a consequence of cancer chemo-therapy. Community- and hospital-acquired infec-tious diseases are a part of the progression of many common NCDs. As the burden of diabetes, cancers, and chronic lung diseases rises, the burden of associ-ated community- and hospital-acquired infections will also likely mount. Resistance will make some of them costly, difficult, and sometimes impossible to treat successfully.Further concern stems from the increasingly un-tenable assumption that industry is a ceaseless source of new antibiotics. This faith underlies the courage of many surgeons to undertake operations that put patients at risk of surgical infections. Similarly, oncolo-gists use powerful forms of cancer chemotherapy that undermine the patient’s immune system, believing that antibiotics will rescue those who can’t fend off infections. Second, many NCDs are considered lifestyle diseases. We can choose what we eat, we can choose to exercise, and we can choose whether or not to smoke. The medical establishment or the state gener-ally has only a limited capacity to demand preventive behaviors. So education becomes the tool of persua-sion. Similarly, with respect to mitigating antimicro-bial resistance, legislators and the public also need to

Antimicrobial activity of marine sponges against coagulase-negative staphylococci isolated from bovine mastitis

Bovine mastitis remains worldwide a major challenge for the dairy industry despite the widespread implementation of control strategies. The increasing number of coagulase-negative staphylococci (CNS) causing mastitis and of bacteria resistant to conventional antibiotics has become a serious problem in recent years. Marine sponges are a rich source of bioactive compounds, and many species can be useful for the development of new antimicrobial drugs. In the present study, 49 CNS strains were isolated from bovine mastitis cases from 21 different dairy herds kept at farms in Southeast Brazil. Strains were analyzed for antimicrobial susceptibility and mecA gene detection. Fifty-nine percent of the CNS strains were resistant to at least one of the drugs tested and 12.2% were classified as multiresistant. Three strains carried the mecA gene, confering resistance to the beta-lactamic antibiotics. In addition, the CNS strains were submitted to in vitro screening for antimicrobial activities of extracts from marine sponges. Extracts from the sponge species Cinachyrella sp., Haliclona sp. and Petromica citrina showed antibacterial activity against 61% of the CNS strains, including strains resistant to conventional antibiotics. Extracts from P. citrina showed the largest spectrum of inhibitory activity. The aqueous extract inhibited 51% of the CNS strains and presented a bactericidal effect over susceptible and multiresistant-bacteria at a minimal inhibitory concentration of 1.024μg/ml. This study shows the potential of marine sponges as new sources of antibiotics and disinfectants for the control of CNS involved in bovine mastitis.

Development of a vector and host system and characterization of replication of plasmid pSQ10 in moderately halophilic <italic>Nocardiopsis</italic>

The genus of Nocardiopsis is a new source of antibiotics, chemicals, and enzymes. Here we reported the development of a vector and host system in moderately halophilic Nocardiopsis via an oriT-mediated conjugation. By screening about 80 Nocardiopsis strains, 6 of them harbored 8 plasmids (18-80 kb). The complete nucleotide sequence of pSQ10 consisted of 18,219 bp, with 71.9% G + C content, encoding 17 open reading frames, 5 of them resembled those of Streptomyces plasmids. A rep locus (iteron within the gene) was identified for replication in Nocardiopsis sp. YIM 90083, and rep protein bound to its iteron sequence. This system may be useful for gene cloning and expression in Nocardiopsis.

Novel bioactive metabolites producing endophytic fungusColletotrichum gloeosporioidesagainst multidrug-resistantStaphylococcus aureus

The emergence of antibiotic-resistant bacteria such as Staphylococcus aureus calls for inventive research and development strategies. Inhibition of this bacterial pathogenesis may be a promising therapeutic approach. The screening of antimicrobial compounds from endophytes is a promising way to meet the increasing threat of drug-resistant strains of human and plant pathogens. In the present study, a novel endophytic fungus, Colletotrichum gloeosporioides, was isolated from the medicinal plant Vitex negundo L. Extracts of C. gloeosporioides were obtained using hexane, ethyl acetate and methanol solvents. The fungal extracts exhibited an effective antimicrobial activity against bacterial and fungal strains. The extracts were also analysed for antibacterial activity against methicillin-, penicillin- and vancomycin-resistant S. aureus strains (1-10). The methanol extract showed an effective antibacterial activity against S. aureus strain 9, with a minimal inhibitory concentration of 31.25 μg mL(-1) . The synergistic action of endophytic fungal extract with antibiotics such as methicillin, penicillin and vancomycin was observed against S. aureus strain 6. The fractional inhibitory concentration index of methanol extract with methicillin, penicillin and vancomycin was 1.0, 0.5 and 0.375, respectively. These results clearly indicate that the metabolite of endophytic fungus C. gloeosporioides is a potential source of new antibiotics.