Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

Microorganisms are well-known producers of a wide variety of bioactive compounds that are utilized not only for their primary metabolism but also for other purposes such as defense, detoxification, or communication with other micro- and macro-organisms. Natural products containing a 'decalin ring' occur often in microorganisms. They exhibit diverse and remarkable biological activities, including antifungal, antibacterial, anticancer and immunosuppressive activities, to name a few. This review surveys the natural decalin-type compounds that have been isolated from microorganisms, with emphasis on both chemical and biological implications. Total syntheses of some important decalin moiety-containing natural products are also highlighted.

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Objective: to investigate the prevalence and antimicrobial resistance of Enterococcus species isolated from a university hospital, and explore the mechanisms underlying the antimicrobial resistance, so as to provide clinical evidence for the inappropriate clinical use of antimicrobial agents and the control and prevention of enterococcal infections. Methods: a total of 1,157 enterococcal strains isolated from various clinical specimens from January 2010 to December 2012 in the General Hospital of Ningxia Medical University were identified to species level with a VITEK-2 COMPACT fully automated microbiological system, and the antimicrobial susceptibility of Enterococcus species was determined using the Kirby-Bauer disc diffusion method. The multiple-drug resistant enterococcal isolates were screened from the clinical isolates of Enterococcus species from the burns department. The minimal inhibitory concentration (MIC) of Enterococcus species to the three fluoroquinolones, including ciprofloxacin, gatifloxacin and levofloxacin was determined with the agar dilution method, and the changes in the MIC of Enterococcus species to the three fluoroquinolones following reserpine treatment were evaluated. The β-lactam, aminoglycoside, tetracycline, macrolide, glycopeptide resistance genes and the efflux pump emeA genes were detected in the enterococcal isolates using a polymerase chain reaction (PCR) assay. Results: the 1,157 clinical isolates of Enterococcus species included 679 E. faecium isolates (58.7%), 382 E. faecalis isolates (33%), 26 E. casseliflavus isolates (2.2%), 24 E. avium isolates (2.1%), and 46 isolates of other Enterococcus species (4%). The prevalence of antimicrobial resistance varied significantly between E. faecium and E. faecalis, and ≤1.1% of these two Enterococcus species were found to be resistant to vancomycin, teicoplanin or linezolid. In addition, the Enterococcus species isolated from different departments of the hospital exhibited various resistances to the same antimicrobial agent, while reserpine treatment reduced the resistance of Enterococcus species to ciprofloxacin, gatifloxacin and levofloxacin. The β-lactamase gene TEM, aminoglycoside-modifying-enzyme genes aac(6')-aph(2"), aph(3')-III, ant(6)-I and ant(2")-I, tetracycline resistance gene tetM, erythromycin resistance gene ermB, vancomycin resistance gene vanA and the enterococcal multidrug resistance efflux emeA gene were detected in 77%, 62%, 26%, 13%, 36%, 31%, 66%, 5% and 55% of the 100 multiple-drug resistant enterococcal isolates. Conclusions: similar to previous findings, E. faecium and E. faecalis are predominant conditionally pathogenic bacteria that cause hospital-acquired infections that can cause urinary and respiratory system infections. Multiple and high-level antimicrobial resistance is highly prevalent in the hospital isolates of Enterococcus species. Reserpine treatment inhibits the active efflux of Enterococcus species to ciprofloxacin, gatifloxacin and levofloxacin in vitro and reduces the MIC of Enterococcus species...

c Fifty-seven carbapenem-resistant Klebsiella pneumoniae isolates belonging to ST11 (50 isolates), ST423 (5 isolates), and two other sequence types were studied. All were positive for bla KPC-2 , bla TEM-1 , and bla CTX-M-14 . SDS-PAGE analysis of six representative isolates demonstrated varied porin expression. Nevertheless, when bla KPC-2 was deleted, carbapenem resistance was markedly reduced. Additionally, SHV-12, DHA-1, and/or VIM-1 appeared to contribute to accessory carbapenemase activity. In contrast, OmpK35 and/or OmpK36 deficiency seemed to serve only as a minor cooperative factor. Table S1 in the supplemental material for primer details). Standard multilocus sequence typing (MLST) protocols were utilized, with alternative primers for gapA, mdh, rpoB, and tonB used as required. Fifty isolates belonged to ST11, five belonged to ST423, and one each belonged to ST65 and a novel MLST type, ST977. The first carbapenem-resistant isolate, derived from a urine specimen obtained in August 2006, belonged to ST423. However, only four other ST423 isolates were detected over the study period. In contrast, ST11 remained endemic throughout this period. Intriguingly, isolates belonging to ST65 and ST977 appeared only once. Except for XJ-2 and XJ-4, which exhibited lower carbapenem MICs, all 57 isolates showed high-level resistance to ampicillin, cefotaxime, ceftazidime, imipenem, meropenem, and ertapenem. PCR analysis suggested that all but two isolates produced TEM-1, KPC-2, CTX-M-14, and SHV-12; bla was not detected in XJ-1 and XJ-4. In addition, all five ST423 isolates encoded DHA-1, and the XJ-5 (ST11) isolate uniquely produced VIM-1. CIsolates XJ-1, XJ-2, and XJ-3, representative of ST977, ST65, and ST423, respectively, were chosen for further analysis together with three ST11 isolates: XJ-4 because it had relatively low carbapenem MICs, XJ-5 because it had a supplementary bla VIM-1 gene, and XJ-6 because it was typical of most ST11 isolates. SDS-PAGE analysis of outer membrane proteins extracted as described previously (10) from cells grown overnight with shaking at 37°C in nutrient broth with or without 10 g/liter NaCl showed that XJ-1 expressed smaller quantities of OmpK36, while OmpK35 production was not detected for XJ-1, XJ-4, and XJ-5 (Fig. 1). Furthermore, as the likely OmpK36 protein bands of XJ-3 and XJ-6 were shifted upwards (see below for details), the status of OmpK35 bands in these strains could not be determined (Fig. 1).Although DNA mutations relative to that of NTUH-K2044 were detected in the ompK35 sequences of XJ-4, XJ-5, and XJ-6, no amino acid changes were predicted (Fig. 2). In contrast, the predicted OmpK35 of XJ-1 exhibited 25 amino acid substitutions and a single insertion, while the corresponding sequence of XJ-2 varied by a single amino acid substitution only. The OmpK35 protein of XJ-3 lacked a five-amino-acid string (EIYNK), which mapped to the B1 ␤-sheet. This string of amino acids was strictly conserved in the OmpK35 sequences of the remaining five clinical isolates, NTUH-K2044, a...