A Specific Oxidative Catastrophe Three different classes of antibiotics induce bacterial cell death by the production of hydroxyl radicals. Hydroxyl radicals are powerful oxidizing agents in living cells and will oxidize the nucleic acid base, guanine, to form 8-oxoguanine, which is potentially mutagenic because it can pair with both cytosine and adenine and form lethal double-strand DNA breaks. Foti et al. (p. 315) discovered that overproduction of the nucleotide sanitizer MutT, which hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, gives striking protection against cell death. Several antibiotics kill bacteria by causing oxidative damage to guanine nucleotides, which then damage nucleic acids. A detailed understanding of the mechanisms that underlie antibiotic killing is important for the derivation of new classes of antibiotics and clinically useful adjuvants for current antimicrobial therapies. Our efforts to understand why DinB (DNA polymerase IV) overproduction is cytotoxic to Escherichia coli led to the unexpected insight that oxidation of guanine to 8-oxo-guanine in the nucleotide pool underlies much of the cell death caused by both DinB overproduction and bactericidal antibiotics. We propose a model in which the cytotoxicity of beta-lactams and quinolones predominantly results from lethal double-strand DNA breaks caused by incomplete repair of closely spaced 8-oxo-deoxyguanosine lesions, whereas the cytotoxicity of aminoglycosides might additionally result from mistranslation due to the incorporation of 8-oxo-guanine into newly synthesized RNAs.

Oxidation of the Guanine Nucleotide Pool Underlies Cell Death by Bactericidal Antibiotics

Natural products derived from microorganisms serve as a vital resource of valuable pharmaceuticals and therapeutic agents. Streptomyces is the most ubiquitous bacterial genus in the environments with prolific capability to produce diverse and valuable natural products with significant biological activities in medicine, environments, food industries, and agronomy sectors. However, many natural products remain unexplored among Streptomyces. It is exigent to develop novel antibiotics, agrochemicals, anticancer medicines, etc., due to the fast growth in resistance to antibiotics, cancer chemotherapeutics, and pesticides. This review article focused the natural products secreted by Streptomyces and their function and importance in curing diseases and agriculture. Moreover, it discussed genomic-driven drug discovery strategies and also gave a future perspective for drug development from the Streptomyces.

/pdf/streptomyces-the-biofactory-of-secondary-metabolites-1ihqff71.pdf

Streptomyces: The biofactory of secondary metabolites

The Streptomyces genus has been a rich source of bioactive natural products, medicinal chemicals, and novel drug leads for three-quarters of a century. Yet studies suggest that the genus is capable of making some 150,000 more bioactive compounds than all Streptomyces secondary metabolites reported to date. Researchers around the world continue to explore this enormous potential using a range of strategies including modification of culture conditions, bioinformatics and genome mining, heterologous expression, and other approaches to cryptic biosynthetic gene cluster activation. Our survey of the recent literature, with a particular focus on the year 2020, brings together more than 70 novel secondary metabolites from Streptomyces species, which are discussed in this review. This diverse array includes cyclic and linear peptides, peptide derivatives, polyketides, terpenoids, polyaromatics, macrocycles, and furans, the isolation, chemical structures, and bioactivity of which are appraised. The discovery of these many different compounds demonstrates the continued potential of Streptomyces as a source of new and interesting natural products and contributes further important pieces to the mostly unfinished puzzle of Earth’s myriad microbes and their multifaceted chemical output.

/pdf/recently-discovered-secondary-metabolites-from-streptomyces-3d3wbha7.pdf

Recently Discovered Secondary Metabolites from Streptomyces Species

황색포도알균은 지역사회와 병원에서 발생하는 감염증 의 가장 중요한 원인균으로 그간 항생제 개발 및 내성의 역사와 그 궤적을 같이 하였다 1) . 항생제가 사용되기 전인 1940년 이전에는 황색포도알균 감염증의 사망률이 90%에 달했지만, 페니실린 항생제가 도입되면서 사망률은 급격 하게 떨어졌다. 그러나 페니실린을 사용하기 시작한지 10 년도 지나지 않아 황색포도알균 대부분이 페니실린에 듣 지 않게 되었다. 이러한 내성균주를 치료하기 위해 황색포 도알균이 분비하는 베타락탐분해효소에도 분해되지 않는 반합성 베타락탐 항생제인 methicillin이 1960년에 개발되 었지만, 곧 이 항생제에도 듣지 않는 methicillin-resistant S. aureus (MRSA)가 출현하였다. MRSA는 1961년 영국 에서 처음 출현하였으며, 1970년대 말부터 영국과 호주 등 지에서 새로운 유행균주 (EMRSA1)가 등장한 이후 전 세 계적으로 빈도가 급격히 증가하였고 1980년에 들어서는 병원내에 만연하게 되었다 2) . 최근에는 반코마이신에 감수 성이 저하된 균주 (VISA, vancomycin-intermediate S. aureus) 3, 4) 와 반코마이신에 전혀 듣지 않는 균주(VRSA, vancomycin-resistant S. aureus) 5-7) 가 보고되기도 하였다. 우리나라의 경우 1960년대에는 MRSA의 분리보고가 없었지만, 1977년 박 등이 5%의 MRSA 빈도를 보고한 이래 1980년도부터 급격히 증가하기 시작하였다. 최근에 는 우리나라 대부분의 종합병원이나 대학병원에서 분리 되는 S. aureus 균주 중 MRSA의 비율이 60~70%를 상 회하는 것으로 알려져 있다 8, 9) . 또한, MRSA는 우리나라 에서 발생하는 병원감염의 주요 원인균이다. 1997년 300 병상 이상 규모의 69개 병원을 대상으로 조사한 대한병 원감염관리학회의 보고에 따르면 우리나라 병원감염의 가장 흔한 원인균은 S. aureus (17.2%)였으며, 이 중 78.8%가 MRSA로 가장 흔하였다. 감염부위별로도 S. aureus는 수술부위감염(28.3%), 폐렴(23.5%), 균혈증 (15.5%)의 가장 흔한 원인균이었다 10) . 이처럼 MRSA는 항생제를 많이 사용하는 병원 환경 에서 발생한 황색포도알균 감염증의 주된 원인이며 건 강한 지역사회 거주인들 가운데서는 그 보균율이 매우 낮은 것으로 알려져 왔다. 과거 드물게 MRSA에 의한 지역사회 감염증이 보고되었지만, 1980년에 처음 발생한 예는 마약중독자(intravenous drug addicts)에서 발생한 것이었다. 하지만 1997년부터 1999년 사이에 미국 Minnesota와 North Dakota에서 건강한 4명의 어린이가 중증 패혈증으로 사망하였으며 12) , 원인병원체가 모두 MRSA라는 사실이 알려지면서 지역사회관련 MRSA에 대한 관심이 높아지기 시작하였다. 최근 외국에서 문제가 되고 있는 지역사회관련 MRSA 감염증은 기저질환이 없 는 건강한 사람에서 생긴다는 것이 이전과 큰 차이이다.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)

Plants and associated microorganisms are essential sources of natural products against human cancer diseases, partly exemplified by plant-derived anticancer drugs such as Taxol (paclitaxel). Natural products provide diverse mechanisms of action and can be used directly or as prodrugs for further anticancer optimization. Despite the success, major bottlenecks can delay anticancer lead discovery and implementation. Recent advances in sequencing and omics-related technology have provided a mine of information for developing new therapeutics from natural products. Artificial intelligence (AI), including machine learning (ML), has offered powerful techniques for extensive data analysis and prediction-making in anticancer leads discovery. This review presents an overview of current AI-guided solutions to discover anticancer lead compounds, focusing on natural products from plants and associated microorganisms. 

Artificial intelligence-guided discovery of anticancer lead compounds from plants and associated microorganisms

As demands for new antibiotics and strategies to control methicillin-resistant Staphylococcus aureus (MRSA) increase, there have been efforts to obtain more accurate and abundant information about the mechanism of the bacterial responses to antibiotics. However, most of the previous studies have investigated responses to antibiotics without considering the genetic differences between MRSA and methicillin-susceptible S. aureus (MSSA). Here, we initially applied a multi-omics approach into the clinical isolates (i.e., S. aureus WKZ-1 (MSSA) and S. aureus WKZ-2 (MRSA)) that are isogenic except for the mobile genetic element called staphylococcal cassette chromosome mec (SCCmec) type IV to explore the response to β-lactam antibiotics (oxacillin). First, the isogenic pair showed a similar metabolism without oxacillin treatment. The quantitative proteomics demonstrated that proteins involved in peptidoglycan biosynthesis (MurZ, PBP2, SgtB, PrsA), two-component systems (VrsSR, WalR, SaeSR, AgrA), oxidative stress (MsrA1, MsrB), and stringent response (RelQ) were differentially regulated after the oxacillin treatment of the isogenic isolates. In addition, targeted metabolic profiling showed that metabolites belonging to the building blocks (lysine, glutamine, acetyl-CoA, UTP) of peptidoglycan biosynthesis machinery were specifically decreased in the oxacillin-treated MRSA. These results indicate that the difference in metabolism of this isogenic pair with oxacillin treatment could be caused only by SCCmec type IV. Understanding and investigating the antibiotic response at the molecular level can, therefore, provide insight into drug resistance mechanisms and new opportunities for antibiotics development.

/pdf/multi-omics-based-characterization-of-antibiotic-response-in-4fz1wdb3u9.pdf

Multi-omics based characterization of antibiotic response in clinical isogenic isolates of methicillin-susceptible/-resistant Staphylococcus aureus

Phenol-soluble modulins (PSMs) are major determinants of Staphylococcus aureus virulence and their increased production in community-associated methicillin-resistant S. aureus (CA-MRSA) likely contributes to the enhanced virulence of MRSA strains. Here, we analyzed the differences in bacterial cell aggregation according to PSM presence in the specific human cerebrospinal fluid (CSF) environment. CSF samples from the intraventricular or lumbar intrathecal area of each patient and tryptic soy broth media were mixed at a 1:1 ratio, inoculated with WT and PSM-deleted mutants (Δpsm) of the CA-MRSA strain, USA300 LAC, and incubated overnight. Cell aggregation images were acquired after culture and image analysis was performed. The cell aggregation ratio in WT samples differed significantly between the two sampling sites (intraventricular: 0.2% vs. lumbar intrathecal: 6.7%, p < 0.001). The cell aggregation ratio in Δpsm samples also differed significantly between the two sampling sites (intraventricular: 0.0% vs. lumbar intrathecal: 1.2%, p < 0.001). Division of the study cases into two groups according to the aggregated area ratio (WT/Δpsm; group A: ratio of ≥ 2, group B: ratio of < 2) showed that the median aggregation ratio value differed significantly between groups A and B (5.5 and 0, respectively, p < 0.001). The differences in CSF distribution and PSM presence within the specific CSF environment are significant factors affecting bacterial cell aggregation.

https://www.mdpi.com/2073-4409/9/3/788/pdf

Phenol-Soluble Modulin-Mediated Aggregation of Community-Associated Methicillin-Resistant Staphylococcus Aureus in Human Cerebrospinal Fluid.

Two new unique angucyclinones (1 and 2) with unprecedented ether bridges connecting carbons 5 and 7 were isolated from the cultures of Streptomyces bulli GJA1, an endophyte of Gardenia jasminoides, together with two known ones (3 and 4). The MS2-based molecular networking system facilitated the isolation of compounds with target functionalities. The stereochemistry of 1 was completely established by ROESY and ECD experiments. Compound 3 showed antivirulence activities by inhibiting the peptide toxin (PSMs) production and the biofilm formation of MRSA. Compounds 3 and 4 showed very potent anti-proliferative effects against OV1 and ES2 ovarian cancer cells.

Unusual bridged angucyclinones and potent anticancer compounds from Streptomyces bulli GJA1.

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Multi-omics based characterization of antibiotic response in clinical isogenic isolates of methicillin-susceptible/-resistant Staphylococcus aureus

Phenol-Soluble Modulin-Mediated Aggregation of Community-Associated Methicillin-Resistant Staphylococcus Aureus in Human Cerebrospinal Fluid.

Unusual bridged angucyclinones and potent anticancer compounds from Streptomyces bulli GJA1.