Propensity For Resistance Development Research Articles

Propensity for resistance development in the invasive berry pest, spotted-wing drosophila (Drosophila suzukii), under laboratory selection.

Over the past 14 years, the invasive vinegar fly, spotted-wing drosophila (Drosophila suzukii), has become one of the most damaging fruit pests in the United States. With regional economic losses estimated as high as $500million for moderate infestations, D. suzukii control represents an often-untenable cost to growers. Management relies heavily on chemical control, which may be applied up to nine times in one season. The widespread use of chemical controls has led to concerns about insecticide resistance, and resistant field populations have already been documented in California and Michigan. We cultured sub-populations of three different Minnesota field populations of D. suzukii in the laboratory and exposed them to increasing concentrations of two commonly-used insecticides, zeta-cypermethrin (pyrethroid) and spinetoram (spinosyn). Over the exposure period, the sub-populations experienced an 8- to 45-fold increase in insecticide concentration. We saw significant increases in the median lethal concentration (LC50 ) values of one sub-population exposed to zeta-cypermethrin and one exposed to spinetoram. Across the spinetoram exposures, we also observed significant reductions in the top mortality values for three different sub-populations. Our results suggest that field populations of D. suzukii can develop resistance to zeta-cypermethrin and spinetoram in short periods of time under laboratory selection but that resistance to spinosyns occurs more readily than to pyrethroids. These results support other studies that have documented spinosyn resistance in field populations and in laboratory selections. Resistance evolution to spinosyns is a particularly important issue, as they represent one of few organic insecticide options for D. suzukii. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Antimicrobial blue light: A 'Magic Bullet' for the 21st century and beyond?

Over the past decade, antimicrobial blue light (aBL) at 400- 470nm wavelength has demonstrated immense promise as an alternative approach for the treatment of multidrug-resistant infections. Since our last review was published in 2017, there have been numerous studies that have investigated aBL in terms of its, efficacy, safety, mechanism, and propensity for resistance development. In addition, researchers have looked at combinatorial approaches that exploit aBL and other traditional and non-traditional therapeutics. To that end, this review aims to update the findings from numerous studies that capitalize on the antimicrobial effects of aBL, with a focus on: efficacy of aBL against different microbes, identifying endogenous chromophores and targets of aBL, Resistance development to aBL, Safety of aBL against host cells, and Synergism of aBL with other agents. We will also discuss our perspective on the future of aBL.

Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.

Evaluation of a Dual-Acting Antibacterial Agent, TNP-2092, on Gut Microbiota and Potential Application in the Treatment of Gastrointestinal and Liver Disorders.

TNP-2092 is a unique multitargeting drug conjugate with extremely low propensity for development of resistance. The in vitro activity of TNP-2092 against a panel of urease-producing bacteria was similar to that of rifaximin, a locally acting antibiotic approved for the treatment of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and traveler's diarrhea. When given orally, TNP-2092 exhibited low absorption and the majority of compound was recovered in feces as parent. The impact of oral TNP-2092 on gut microbiota was investigated in rats. TNP-2092 was administered to rats by oral gavage for 7 days. Feces samples were collected and analyzed by 16S rRNA sequencing. Although the total amount of bacterial load appeared relatively unchanged before, during, and after treatment, significant changes in the relative abundance of certain gut bacteria at family and genus levels were observed. Some of the changes are known to be associated with improvement of symptoms associated with liver cirrhosis and hepatic encephalopathy. The observed effects of TNP-2092 on gut microbiota in rats were similar to those of rifaximin. In vivo, TNP-2092 demonstrated potent efficacy in a mouse Clostridium difficile infection model, superior to metronidazole and vancomycin, with no relapse observed after treatment. TNP-2092 is currently in clinical development for the treatment of symptoms associated with gastrointestinal and liver disorders.

Constitutive expression of antimicrobial peptide PR-39 in transgenic mice significantly enhances resistance to bacterial infection and promotes growth.

Use of huge amounts of antibiotics in farm animal production has promoted the prevalence of antibiotic-resistant bacteria, which poses a serious threat to public health. Therefore, alternative approaches are needed to reduce or replace antibiotic usage in the food animal industry. PR-39 is a pig-derived proline-rich antimicrobial peptide that has a broad spectrum of antibacterial activity and a low propensity for development of resistance by microorganisms. To test whether ubiquitous expression of PR-39 in transgenic (TG) mice can increase resistance against bacterial infection, we generated TG mice that ubiquitously express a pig-derived antimicrobial peptide PR-39 and analyzed their growth and resistance to infection of the highly pathogenic Actinobacillus pleuropneumoniae (APP) isolated from swine. The growth performance was significantly increased in TG mice compared with their wild-type (WT) littermates. After the APP challenge, TG mice exhibited a significantly higher survival rate and significantly lower tissue bacterial load than WT littermates. Furthermore, the tissue lesion severity that resulted from APP infection was milder in TG mice than that in their WT littermates. This study provides a good foundation for the development of PR-39-expressing TG animals, which could reduce the use of antibiotics in the farm animal industry.

Analogues of Human Granulysin as Antimycobacterial Agents

Fil: Siano, Alvaro Sebastian. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

Antimicrobial Peptides as Potential Alternatives to Antibiotics in Food Animal Industry.

Over the last decade, the rapid emergence of multidrug-resistant pathogens has become a global concern, which has prompted the search for alternative antibacterial agents for use in food animals. Antimicrobial peptides (AMPs), produced by bacteria, insects, amphibians and mammals, as well as by chemical synthesis, are possible candidates for the design of new antimicrobial agents because of their natural antimicrobial properties and a low propensity for development of resistance by microorganisms. This manuscript reviews the current knowledge of the basic biology of AMPs and their applications in non-ruminant nutrition. Antimicrobial peptides not only have broad-spectrum activity against bacteria, fungi, and viruses but also have the ability to bypass the common resistance mechanisms that are placing standard antibiotics in jeopardy. In addition, AMPs have beneficial effects on growth performance, nutrient digestibility, intestinal morphology and gut microbiota in pigs and broilers. Therefore, AMPs have good potential as suitable alternatives to conventional antibiotics used in swine and poultry industries.