Antimicrobial Natural Products

Although the first antibiotic, penicillin, was discovered in 1928 from a microbial natural source (a mould, Penicillium notatum), there is earlier evidence of using natural materials including moulds and herbs for the treatment of infections. Following the serendipitous discovery of penicillin by Alexander Fleming, there have been hundreds of antibiotics (natural, semisynthetic and synthetic) discovered for clinical uses. However, the pathogenic organisms have developed resistances to existing antibiotics though various mechanisms. Such antibiotic resistance or antimicrobial resistance (AMR) is a critical problem of today’s healthcare system urging the development of new antibiotics. This chapter has primarily focused into antimicrobial compounds developed through natural routes that are currently available as antibiotics for clinical uses and/or are at various developmental stages within the drug development pipeline for potential treatment of minor and life threatening infections. The chapter also provides an overview on the catastrophic problem of antimicrobial resistance, its causes, how it spreads as well as modes of developing antimicrobial resistance (AMR)

Enteric YaiW is a surface-exposed outer membrane lipoprotein that affects sensitivity to an antimicrobial peptide

yaiW is a previously uncharacterized gene found in enteric bacteria that is of particular interest because it is located adjacent to the sbmA gene, whose bacA ortholog is required for Sinorhizobium meliloti symbiosis and Brucella abortus pathogenesis. We show that yaiW is cotranscribed with sbmA in Escherichia coli and Salmonella enterica serovar Typhi and Typhimurium strains. We present evidence that the YaiW is a palmitate-modified surface exposed outer membrane lipoprotein. Since BacA function affects the very-long-chain fatty acid (VLCFA) modification of S. meliloti and B. abortus lipid A, we tested whether SbmA function might affect either the fatty acid modification of the YaiW lipoprotein or the fatty acid modification of enteric lipid A but found that it did not. Interestingly, we did observe that E. coli SbmA suppresses deficiencies in the VLCFA modification of the lipopolysaccharide of an S. meliloti bacA mutant despite the absence of VLCFA in E. coli. Finally, we found that both YaiW and SbmA positively affect the uptake of proline-rich Bac7 peptides, suggesting a possible connection between their cellular functions

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Testing for Parameter Instability in Competing Modeling Frameworks

We develop a new parameter stability test against the alternative of observation driven generalized autoregressive score dynamics. The new test generalizes the ARCH-LM test of Engle (1982) to settings beyond time-varying volatility and exploits any autocorrelation in the likelihood scores under the alternative. We compare the test's performance with that of alternative tests developed for competing time-varying parameter frameworks, such as structural breaks and observation driven parameter dynamics. The new test has higher and more stable power against alternatives with frequent regime switches or with non-local parameter driven time-variation. For parameter driven time variation close to the null or for infrequent structural changes, the test of Muller and Petalas (2010) performs best overall. We apply all tests empirically to a panel of losses given default over the period 1982--2010 and find significant evidence of parameter variation in the underlying beta distribution

Testing for parameter instability across different modeling frameworks

We develop a new parameter instability test against the alternative of a time-varying parameter. The new test generalizes the seminal ARCH-LM test for a constant variance against the alternative of autoregressive conditional heteroskedasticity to settings with nonlinear time-varying parameters and non-Gaussian distributions. These alternative model settings are unified by the class of score-driven time-varying parameter models. We discuss the performance of our test compared to classic but also to more recent alternative tests, including tests against structural breaks and parameter-driven dynamics. For regime switching and mean-reverting parameter-driven dynamics, the new test has higher and more stable power properties. For more local alternatives and for structural breaks, the recent test by Müller and Petalas (2010) performs best. We provide an application to a heavily unbalanced panel of losses given default for U.S. corporations from 1982 to 2010 and provide evidence of significant parameter instability in the parameters of a static beta distributed model. Key words: time-varying parameters; observation-driven and parameter-driven models; structural breaks; generalized autoregressive score model; regime switching; credit risk