Discovery and characterization of antimycobacterial nitro-containing compounds with distinct mechanisms of action and in vivo efficacy.

Nitro-containing compounds have emerged as important agents in the control of tuberculosis (TB). From a whole-cell high-throughput screen for Mycobacterium tuberculosis (Mtb) growth inhibitors, 10 nitro-containing compounds were prioritized for characterization and mechanism of action studies. HC2209, HC2210, and HC2211 are nitrofuran-based prodrugs that need the cofactor F420 machinery for activation. Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F420-dependent reductase for activation. These nitrofurans also differ from pretomanid in their potent activity against Mycobacterium abscessus. Four dinitrobenzamides (HC2217, HC2226, HC2238, and HC2239) and a nitrofuran (HC2250) are proposed to be inhibitors of decaprenyl-phosphoryl-ribose 2'-epimerase 1 (DprE1), based on isolation of resistant mutations in dprE1. Unlike other DprE1 inhibitors, HC2250 was found to be potent against non-replicating persistent bacteria, suggesting additional targets. Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb in vitro, but a proposed mechanism of action could not be defined. In a pilot in vivo efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.

Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef.

The serine incorporator (SERINC) protein family has five paralogous members with 9-11 transmembrane domains. SERINC5 is a potent host restriction factor and antagonized by HIV-1 Nef and two other retroviral accessory proteins via the lysosomal degradation pathway. Here, we investigated human SERINC4 expression and antiviral mechanisms. Unlike its four paralogs, human SERINC4 is subjected to proteasome-mediated turnover, resulting in ~250-fold lower expression than SERINC5. However, when expression was normalized, human SERINC4 restricted HIV-1 replication as effectively as SERINC5, and SERINC4 was also antagonized by Nef via the lysosomal pathway. Although SERINC4 proteins are conserved within primates or rodents, their N-terminal regions are highly variable across species. Interestingly, unlike human SERINC4, murine SERINC4 was stably expressed but had a very poor antiviral activity. We created stable SERINC4 chimeras by replacing the N-terminal region and found that the 1-34 and 35-92 amino acids determine SERINC4 antiviral activity or protein expression, respectively. Using these chimeras, we demonstrate that SERINC4 is incorporated into HIV-1 virions and restricts Tier 1 HIV-1 more effectively than Tier 3 HIV-1. Importantly, SERINC4 increases HIV-1 sensitivity to broadly neutralizing antibodies. Thus, human SERINC4 strongly restricts HIV-1 replication when it is overexpressed, which reflects a potential antiviral activity of this gene product under physiological conditions.

Principal component analysis reveals microbial biomass carbon as an effective bioindicator of health status of petroleum-polluted agricultural soil.

We investigated a number of microbiological activities in the soil to serve as biomonitoring tools in assessing the ecotoxicity of diesel-contaminated soil samples during the different periods of bioremediation. Sawdust was used as the biostimulant for the biodegradation of artificial diesel-polluted soil samples. Soil microbial population, soil microbial enzymatic activities (catalase, lipase, dehydrogenase, urease, phosphatase and ß-glucosidase), soil microbial biomass carbon (MBC), nitrogen (MBN) and phosphorus (MBP), soil microbial respirometric index and total petroleum hydrocarbon (TPH) concentration were monitored to evaluate the efficiency of the bioremediation process. After a period of 56 d, total petroleum hydrocarbon content reduced from 14,221 to 270 mg/kg. The parameter estimation using the nth-order kinetic model revealed that the first-order rate constants (k) for TPH removal were 4.417 d-1 and 0.2670 d-1 for sawdust-amended and unamended soil, respectively. This implied that, the sawdust amendment resulted in reaction rate 16.5 times faster than unamended soil. Thus, the biological indicators were generally more pronounced in biostimulated soil than the attenuated soil. However, to evaluate the efficiency of the sawdust-assisted bioremediation, principal component analysis, which was used in selecting the most sensitive bioindicators. It was observed that microbial biomass carbon, catalase, lipase and dehydrogenase were the most responsive bioparameters. A positive relationship between TPH removal and the four most sensitive bioparameters suggests that the use of four biological activities have proven to be effective monitoring tools for evaluating the efficiency of a bioremediation strategy.

Composting technology in waste stabilization: On the methods, challenges and future prospects.

Composting technology has become invaluable in stabilization of municipal waste due to its environmental compatibility. In this review, different types of composting methods reportedly applied in waste management were explored. Further to that, the major factors such as temperature, pH, C/N ratio, moisture, particle size that have been considered relevant in the monitoring of the composting process were elucidated. Relevant strategies to improve and optimize process effectiveness were also addressed. However, during composting, some challenges such as leachate generation, gas emission and lack of uniformity in assessing maturity indices are imminent. Here in, these challenges were properly addressed and some strategies towards ameliorating them were proffered. Finally, we highlighted some recent technologies that could improve composting.