Brasilicardin A (BraA) is a natural diterpene glycoside isolated from the pathogenic actinomycete Nocardia brasiliensis IFM 0406 with highly potent immunosuppressive activity (IC₅₀=0.057 μg/mL). BraA potently inhibits the uptake of amino acids that are substrates for amino acid transport system L of T cells, which is different from the existing clinical immunosuppressants. BraA is more potent in a mouse mixed lymphocyte reaction and less toxic against various human cell lines compared with the known clinical immunosuppressants, such as cyclosporin A, ascomycin and tacrolimus. Therefore, BraA attracted more attention as a new promising immunosuppressant. However, the development of this promising immunosuppressant as drug for medical use is so far hindered because BraA has the unusual and synthetically challenging skeleton and shows the low-yield production in the natural pathogenic producer. This review introduces the molecular structure of BraA, its activity, mechanism of action, chemical synthesis of BraA analogs, heterologous expression of gene cluster, and an application of combining microbial and chemical synthesis for production of BraA, with the aim to facilitate the efficient production of BraA and its analogs.
Animals ; Mice ; Humans ; Immunosuppressive Agents/chemistry* ; Aminoglycosides/pharmacology* ; Cyclosporine/pharmacology* ; Diterpenes

Evidence suggests that otologic injury from ototopical aminoglycoside preparations is infrequent when used to treat ear infections with an intact tympanic membrane. Meanwhile, parenteral administration of aminoglycosides, is well known to be associated with a significant incidence of cochlear and vestibular damage. The discrepancy between topical and parenteral ototoxic effects is thought to result from a combination of factors, including the protective function of debris overlying the round window membrane, low antibiotic concentrations of topical antibiotic preparations, length of exposure and inability to detect subtle hearing or vestibular changes. Herein, we present a case of acute vestibulopathy following a 2-week course of topical gentamicinotic drops. Awareness of vestibulotoxicity following topical gentamicin therapy is prudent as vestibulopathic symptoms can be severely debilitating.
Aminoglycosides ; Ototoxicity

Nature, a rich source of bioactive natural products, serves as a massive pool of drug candidates for the pharmaceutical industry. However, the supply of these structurally complex chemicals is costly as most of the natural products are scarce in nature, thus requiring de novo synthesis. The supply chain issue hinders the development of novel therapeutic agents from natural products. Microbial synthesis, based on the expression of biosynthetic genes in a suitable microbial host to produce certain chemicals, is a sustainable strategy to produce complex natural products. However, this strategy requires gaining insights into the biosynthesis of target molecules. Most natural products are biosynthetically unknown or not fully elucidated; thus, the sole application of microbial synthesis strategy to produce a given molecule is challenging. In this review, we highlight a strategy that combines microbial and chemical syntheses to tackle the supply chain issue in developing drugs from natural products. We believe this strategy can revive the drug development pipeline for natural products.
Biological Products/chemistry* ; Aminoglycosides

For the purpose of seeking new antibiotics, researchers usually modify the already-existing ones. However, this strategy has been extensively used and is close to its limits, especially in the case of aminoglycosides, and it is difficult to find a proper aminoglycoside antibiotic for novel modification. In this paper, we reported the design, synthesis, and evaluation of a series of 5-epi-neamine derivatives based on the structural information of bacterial 16S RNA A-site binding with aminoglycosides. Bioassay results showed that our design strategy was feasible. Our study offers a new way to search for structurally novel aminoglycosides. Meanwhile, our study provides valuable structure-activity relationship information, which will lead to better understanding and exploitation of the drug target, and improved development of new aminoglycoside antibiotics.
Aminoglycosides/chemistry* ; Anti-Bacterial Agents/chemistry* ; RNA, Ribosomal, 16S/metabolism* ; Structure-Activity Relationship ; Biological Assay

Antibacterial drugs are one of the most important therapeutic agents of bacterial infections but multidrug resistant Escherichia coli (MDREC) is an increasing problem worldwide. Major resistance mechanism of MDREC is horizontal gene transfer of R plasmids harboring integrons, which the integron integrase (IntI) catalyzes gene cassette insertion and excision through site specific recombination. In this study, resistance profiles of integron harboring E. coli isolated in Korea and the genetic environments of integron gene cassettes were analyzed by PCR and direct sequencing to clarify the mechanisms of spread of integron harboring E. coli. Resistance rates of integron harboring E. coli, including β-lactams, aminoglycosides, and fluoroquinolones and MDR frequencies were significantly higher than that of E. coli without integron (p < 0.01). Majority (80%) of integron harboring E. coli showed resistance transfer by conjugation. Most (80%) of E. coli had dfrA17-aadA5 cassette array and PcH1 hybrid promoter; 16.7% of E. coli had dfrA12-orfF-aadA2 cassette array and PcW promoter. The higher prevalence of weak Pc variants among most (96.7%) of integron harboring MDREC suggests that a flexible cassette array is more important than enhanced expression. All the integrons had LexA binding motif suggests that SOS responses control the expression of these integrons. In conclusion, the genetic bases of integrons were diverse, and the spread and the expression of prevalent gene cassette arrays may be deeply related with strengths of Pc promoters in integrons. These informations will provide important knowledge to control the increase of integron harboring MDREC.
Aminoglycosides ; Bacterial Infections ; Escherichia coli ; Escherichia ; Fluoroquinolones ; Gene Transfer, Horizontal ; Integrases ; Integrons ; Korea ; Polymerase Chain Reaction ; Prevalence ; R Factors ; Recombination, Genetic ; SOS Response (Genetics)

The production of rmtB-encoded 16S rRNA methylases has emerged as a novel mechanism promoting high-level resistance toward aminoglycosides in Gram-negative bacteria. Between 2015 and 2017, 636 distinct commensal Escherichia (E.) coli isolates were collected from different farms in South Korea to determine the prevalence and molecular characteristics of rmtB. The positive rates of rmtB between all the isolates and amikacin-resistant isolates were 1.1 and 100%, respectively. High-level aminoglycoside resistance could be transferred by conjugation from rmtB-positive donors to higher amikacin-resistance efficacies. This is the first report of 16S rRNA methylase-encoding genes in E. coli isolated from food-producing animals in Korea.
Agriculture ; Amikacin ; Aminoglycosides ; Animals ; Escherichia coli ; Escherichia ; Gram-Negative Bacteria ; Humans ; Korea ; Prevalence ; Tissue Donors

Increasing resistance due to the production of extended-spectrum β-lactamase (ESBL) in Escherichia coli is a major problem to public health and CTX-M enzymes have become the most prevalent ESBL worldwide. In this study, resistance profiles of E. coli isolated in Korea and the genetic environments of bla(CTX-M) genes were analyzed by PCR and direct sequencing to clarify the mechanisms of spread of CTX-M. Resistance rates of CTX-M-producing E. coli, including β-lactams, fluoroquinolones and aminoglycosides, were significantly higher than that of CTX-M-non-producers (p<0.01). Of 41 tested, 39 (95.1%) isolates of CTX-M-producing E. coli showed resistance transfer by conjugation. All the transconjugants harboured large plasmids of 118~172 megadalton. Insertion sequence ISEcp1B was detected in the upstream of the bla(CTX-M) in 38 (92.7%) isolates with bla(CTX-M). ISEcp1B was disrupted by IS26 in 16 (39.0%) isolates with bla(CTX-M). ISEcp1B carried −35 and −10 promoter components between right inverted repeat (IRR) and the start codon of bla(CTX-M). orf477 or IS903D was observed in the downstream of the bla(CTX-M) in all the isolates with bla(CTX-M-3/15/55) or with bla(CTX-M-14/27), respectively. Sequence similar to IRR of ISEcp1B was located downstream of orf477. Target duplication sequences were detected both upstream of IRL and downstream of IRR. These results showed the involvement of ISEcp1B in the mobilization of the resistance genes. In conclusion, the surrounding DNAs of bla(CTX-M) genes were very diverse, and the spread and the expression of CTX-M may be deeply related with ISEcp1B. These informations will provide important knowledge to control the increase in CTX-M-ESBLs.
Aminoglycosides ; Codon, Initiator ; DNA ; Escherichia coli ; Escherichia ; Fluoroquinolones ; Korea ; Plasmids ; Polymerase Chain Reaction ; Public Health

OBJECTIVES: Antimicrobial resistant extended-spectrum-β-lactamase-producing Enterobacteriaceae (ESBL-PE) have been shown to be present in healthy communities. This study examined healthy children from the rural Andean village of Llano del Hato, Mérida, Venezuela, who have had little or no antibiotic exposure to determine the prevalence of fecal carriage of ESBL-producing Escherichia coli (ESBL-EC). METHODS: A total of 78 fecal samples were collected in healthy children aged from 1 to 5 years. ESBL-EC were selected in MacConkey agar plates with cefotaxime and further confirmed by the VITEK 2 system. ESBL were phenotypically detected and presence of bla genes and their variants were confirmed by molecular assays. Determination of phylogenetic groups was performed by PCR amplification. Risk factors associated with fecal carriage of ESBL-EC-positive isolates were analyzed using standard statistical methods. RESULTS: Of the 78 children studied, 27 (34.6%) carried ESBL-EC. All strains harbored the bla(CTX-M-15) allele. Of these, 8 were co-producers of bla(TEM-1), bla(TEM-5), bla(SHV-5) or bla(SHV-12). Co-resistance to aminoglycosides and/or fluoroquinolones was observed in 9 strains. 51.9% of ESBL-EC isolates were classified within phylogroup A. A significant, positive correlation was found between age (≥2.5 – ≤5 years), food consumption patterns and ESBL-EC fecal carriage. CONCLUSION: This is the first study describing the high prevalence of fecal carriage of ESBL-EC expressing CTX-M-15- among very young, healthy children from a rural Andean village in Venezuela with scarce antibiotic exposure, underlining the importance of this population as a reservoir.
Agar ; Alleles ; Aminoglycosides ; Cefotaxime ; Child ; Enterobacteriaceae ; Escherichia coli ; Escherichia ; Fluoroquinolones ; Humans ; Polymerase Chain Reaction ; Prevalence ; Risk Factors ; Venezuela

The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has become a major problem within the field of healthcare-associated infections worldwide in the last decade. The treatment of infections caused by CRE is challenging, and a consensus strategy has not been established. This article reviews old and new antibiotics for the treatment of CRE, and summarizes the overall mechanisms of resistance, epidemiology, diagnosis, and infection control of CRE. For CRE treatment, combination therapies may be preferred. Carbapenem still plays an important role in CRE treatment. Other existing treatment options against CRE include colistin, tigecycline, fosfomycin, and aminoglycosides. New therapeutic options include ceftazidime-avibactam, aztreonam-avibactam, plazomicin, eravacycline, meropenem-vaborbactam, and imipenem-cilastatin-relebactam. Few randomized controlled trials have been conducted, so more studies of new agents against CRE are needed. Because there are relatively few therapeutic options for CRE, adequate infection prevention measures and antimicrobial stewardship are required. Moreover, both personal and national preventive efforts are needed.
Aminoglycosides ; Anti-Bacterial Agents ; Colistin ; Consensus ; Diagnosis ; Enterobacteriaceae ; Epidemiology ; Fosfomycin ; Humans ; Infection Control ; Korea

otrA resembles elongation factor G (EF-G) and is considered to be an oxytetracycline (OTC)-resistance determinant in Streptomyces rimosus. In order to determine whether otrA also conferred resistance to OTC and other aminoglycosides to Streptomyces coelicolor, the otrA gene from S. rimosus M527 was cloned under the control of the strong ermE^* promoter. The resulting plasmid, pIB139-otrA, was introduced into S. coelicolor M145 by intergeneric conjugation, yielding the recombinant strain S. coelicolor M145-OA. As expected S. coelicolor M145-OA exhibited higher resistance levels specifically to OTC and aminoglycosides gentamycin, hygromycin, streptomycin, and spectinomycin. However, unexpectedly, S. coelicolor M145-OA on solid medium showed an accelerated aerial mycelia formation, a precocious sporulation, and an enhanced actinorhodin (Act) production. Upon growth in 5-L fermentor, the amount of intra- and extracellular Act production was 6-fold and 2-fold higher, respectively, than that of the original strain. Consistently, reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that the transcriptional level of pathway-specific regulatory gene actII-orf4 was significantly enhanced in S. coelicolor M145-OA compared with in S. coelicolor M145.
Aminoglycosides/pharmacology* ; Anthraquinones/metabolism* ; Anti-Bacterial Agents/pharmacology* ; Bacterial Proteins/genetics* ; Drug Resistance, Bacterial/genetics* ; Streptomyces coelicolor/metabolism*