Fatty Acid Biosynthesis: an updated review on KAS inhibitors

Since the early twentieth century, with the isolation of penicillin and streptomycin in the 1940s, the modern era of anti-infective drug development has gained momentum. Due to the enormous success of early drug discovery, many infectious diseases were successfully prevented & eradicated. However, this initial hope was wrongheaded, and pathogens evolved as a significant threat to human health. Drug resistance develops as a result of natural selection's relentless pressure, necessitating the identification of new drug targets and the creation of chemotherapeutics that bypass existing drug resistance mechanisms. Fatty acid biosynthesis (FAS) is a crucial metabolic mechanism for bacteria during their growth and development. Several crucial enzymes involved in this biosynthetic pathway have been identified as potential targets for new antibacterial agents. In Escherichia coli (E. coli), this pathway has been extensively investigated. The present review focuses on progress in the development of Kas A, Kas B, and Fab H inhibitors as mono-therapeutic antibiotics.

Isolation of MDCK cells with low expression of mdr1 gene and their use in membrane permeability screening

The Madin-Darby canine kidney (MDCK) cell line is frequently used for permeability screening in drug discovery. It contains endogenous transporters, most prominently canine multidrug resistance P-glycoprotein (Mdr1), which can interfere with studies of P-glycoprotein substrate assessment and permeability measurements. Because MDCK wild type (WT) is genetically heterogeneous, an isolation procedure was investigated in this study to obtain the subclonal line with low P-glycoprotein expression. The best clone obtained had up to 3-fold lower amprenavir efflux and P-glycoprotein expression in comparison to WT. Of 12 standard compounds tested that exhibited active efflux in WT cells, 11 showed a decrease in efflux in the isolated clone. However, the decrease was not below the cut-off value of 2, indicating residual P--glycoprotein activity. Clone isolation via the limiting dilution method, combined with bidirectional amprenavir permeability for clone selection, successfully identified MDCK clones with substantially lower P-glycoprotein efflux and has been demonstrated as a useful tool for assessing passive permeability in early drug discovery.

Accelerating pre-formulation investigations in early drug product lifecycle using predictive methodologies and computational algorithms

Precisely developed computational methodologies can allow the drug product lifecycle process to be time-efficient, cost-effective and reliable through a thorough fundamental understanding at the molecular level. Computational methodologies include computational simulations, virtual screening, mathematical modeling and predictive tools. In light of current trends and increased expectations of product discovery in early pharmaceutical development, we have discussed different case studies. These case studies clearly demonstrate the successful application of predictive tools alone or in combination with analytical techniques to predict the physicochemical properties of drug substances and drug products, thereby shortening research and development timelines. The overall goal of this report is to summarize unique predictive methodologies, which can assist pharmaceutical scientists in achieving time-sensitive research goals and avoiding associated risks that can potentially affect the drug product quality.

A History of Early Drug Sentences in California

The early history of drug sentences in California provides a quintessential example of structural racism in law. The demands of white voters to escalate penalties for drug crimes followed a pattern of collective myth making and value signaling that insisted opiates, cocaine, and cannabis were extremely dangerous, led to other crime, and prevalently were used and sold by immigrants and other despised groups. Public pressure for more severe punishment seemed to peak twice, in the 1920s and 1950s, in response to exaggerated threats such as “dope peddlers” targeting children and profitable “dope rings” controlled by subversive foreigners. Amplified by a self-seeking, robust news media and a multitude of fraternal, civic, and religious organizations, the frightful construction of illicit drugs seemed to demand a simple and uncompromising response: to punish drug users harder by increasing terms of incarceration. But white voters always understood that drug laws targeted immigrants and communities of color, and law enforcers used extreme penalties as leverage to pursue corrupt and racist prerogatives unrelated to reducing drug use. Drug penalties in California were developed over many decades with almost extreme levels of participation by antidrug activists and law enforcers. Appearing somehow scientific, the resulting arrays of penalties implied that the cruelest sentences were reserved for the truly blameworthy, when in fact they were reserved for the marginalized. Moreover, several legal conventions born of these penalty structures—mandatory minimums, the distinction between user and seller, punishment of addiction itself, and presumptions arising from drug quantities—still exacerbate the oppressive nature of drug statutes.