Potential For Development Of Resistance Research Articles

Advancing RNAi for Sustainable Insect Management: Targeted Solutions for Eco-friendly Pest Control

Insect pests pose significant challenges to agriculture, forestry, and public health, causing substantial economic losses and threats to food security. Traditional pest control methods, such as chemical insecticides, have limitations due to the development of insecticide resistance, negative impacts on non-target organisms, and environmental concerns. RNA interference (RNAi) has emerged as a promising approach for developing targeted and environmentally safe insect control strategies. This review explores the potential of RNAi-based methods for pest management, discussing the mechanism of RNAi in insects, factors influencing its efficiency, and various delivery strategies. We highlight the advantages of RNAi, such as species-specific targeting and reduced off-target effects, while also addressing challenges and limitations, including variability in RNAi efficiency among insect species and potential resistance development. The review examines the environmental safety and risk assessment of RNAi-based insect control, current applications, and future prospects. We also discuss the socio-economic impact and public perception of RNAi technology, as well as research gaps and future directions. The integration of RNAi-based insect control into integrated pest management programs is crucial for developing sustainable and effective pest control solutions. By providing a comprehensive overview of the current state and future potential of RNAi-based insect control, this review aims to inform research, policy, and practice in this rapidly evolving field.

Antibiotics in the rice-crayfish rotation pattern: Occurrence, prioritization, and resistance risk

Antibiotics are extensively utilized in aquaculture to mitigate diseases and augment the productivity of aquatic commodities. However, to date, there have been no reports on the presence and associated risks of antibiotics in the emergent rice-crayfish rotation (RCR) system. This study investigated the occurrence, temporal dynamics, prioritization, sources, and potential for resistance development of 15 antibiotics within the RCR ecosystem. The findings revealed that during the crayfish breeding and rice planting periods, florfenicol (FFC) predominated in the RCR's surface water, with peak and average concentrations of 1219.70 ng/L and 57.43 ng/L, and 1280.70 ng/L and 52.60 ng/L, respectively. Meanwhile, enrofloxacin (ENX) was the primary antibiotic detected in RCR soil and its maximum and average concentrations were 624.73 ng/L and 69.02 ng/L in the crayfish breeding period, and 871.27 ng/L and 45.89 ng/L in the rice planting period. Throughout the adjustment period, antibiotic concentrations remained relatively stable in both phases. Notably, antibiotic levels in surface water and soil escalated during the crayfish breeding period and subsided during the rice planting period, with these fluctuations predominantly influenced by FFC and ENX. Source analysis indicated that the antibiotics in RCR predominantly originated from aquaculture activities, supplemented by water exchange processes. Utilizing the entropy utility function and a resistance development model, FFC, clarithromycin (CLR), and roxithromycin (ROX) in surface water, along with ENX, CLR, and ROX in soil, were identified as priority antibiotics. FFC, ENX, and ROX exhibited a medium risk for resistance development. Consequently, this study underscores the necessity to intensify antibiotic usage control during the crayfish breeding period in the RCR system to mitigate environmental risks.

Reviewing the Therapeutic Potential of Plant-based Natural Products Against Multidrug-resistant Bacteria (MDR)

Abstract: The global health of individuals is severely threatened by drug-resistant microorganisms. Existing antibiotics available in the market, such as penicillin, cephalosporins, new β- lactams, aminoglycosides, macrolides, lincomycin, and quinolones, are losing their effectiveness due to overuse and inappropriate prescribing, among other factors. This situation underscores the urgent need to develop new antimicrobial agents. In response to this challenge, attention has been directed towards natural products derived from plants, which have been utilized for their medicinal benefits over an extended period. Various studies have demonstrated that plant-based natural products exhibit antibacterial action against multidrug-resistant (MDR) bacteria, making them potential candidates for the development of novel antimicrobial medicines. Plants belonging to classes, such as alkaloids, organosulfur compounds, terpenoids, coumarin, and polyphenols have been found to possess antimicrobial properties. This paper reviews the antimicrobial activity of plant-based natural products, whether used alone or in combination with conventional antibiotics. Additionally, the paper explores their mechanisms against drugresistant bacteria, the potential development of resistance against them, their current role in medicine, and their future perspectives.

1,2-Diboranes with strong donor substitutes: Synthesis, ovicidal and larvicidal effect on important vector species

Novel control products are needed in the control of important insects like mosquitoes which are developing resistance to insecticides and larvicides currently in the market. Boron compounds have been demonstrated to exhibit antibacterial and anticancer effects. 1,2-diboranes with a long history and importance in boron chemistry have been described. These compounds are synthesized from reactions of 1,2-dichlordiborane derivatives with lidium amides (ArNHLi/Et2NLi, etc.). In addition to the three previously synthesized diborane compounds, five novel 1,2-diborane compounds were synthesized in good yield using the same method for the first time. The structures of the novel derivatives were characterized by nuclear magnetic resonance spectroscopy, and the molecular structure of one of them (2a) was also demonstrated using single crystal X-ray diffraction. In this preliminary study, the ovicidal and larvicidal effects of new 1,2-diamino-1,2-diborane derivatives against Aedes aegypti and Aedes albopictus eggs and larvae were investigated for the first time. Of these, 2a and 2e showed the highest ovicidal activity against both species, while 7, 4 and 2d showed particularly high larvicidal activity. Some 1,2-diborane derivatives were found to be significantly toxic, with LC50 values ranging from 14,930 to 27,975 μg/mL. Some derivatives (6, 2a, 2c) were less effective against mosquito larvae. 1,2-Diborane derivatives have high ovicidal and larvicidal effects on mosquitoes and are therefore potential candidates for the development of new larvicides. Further studies are needed to evaluate its mode of action and safety. Understanding their mode of action against mosquito development is crucial to optimizing their use and reducing the potential development of resistance. Their potential effects on other mosquito species and non-target organisms need to be investigated.

Assessing the effectiveness of intervention to prevent plague through community and animal-based survey.

Bubonic plague, transmitted by infected flea bites, is the most common form of plague and, left untreated, can progress to the pneumonic form, which is highly contagious. Surveillance focusing on reservoir and vector is considered to be the main approach to prevent plague. Common rodent control methods include the use of rodenticide and snap traps but, in a plague context, the dispersal of fleas from killed animals may pose a serious health threat. Therefore, there is a need for strategies which address reservoir and vector control. The aim of this study was to assess the effects of combination of reservoir and vector control through community-based surveillance. Activities were implemented by local previously trained community agents in two active plague foci in Madagascar. Kartman bait stations containing rodenticide and insecticide were placed indoors while live traps were set outdoors. Small mammals were identified and killed with their fleas. Effectiveness of control measures was evaluated by comparison of plague incidence two years before and after intervention using data on reported human cases of plague from the Central Laboratory of Plague. A total of 4,302 small mammals were captured, with the predominance of the black rat Rattus rattus. Our results found a reduction in plague incidence in the treated site for at least two years after treatment. Community-based interventions played an important role in reducing contact between humans-rodents-fleas. Our study confirms the importance of animal surveillance during the low plague transmission season. The combination of reservoir and vector control with community involvement may be effective at reducing the risks of plague spillover to humans. The strategy of using Kartman bait stations indoors with live traps outdoors can be used to refine proactive plague prevention, however, due to the potential development of resistance to pesticides in flea and rat populations, overuse should be considered.

Establishment and application of bioassay- and molecular marker-based methods for monitoring fluvalinate resistance of Varroa mites

The Varroa mite, Varroa destructor, is an ectoparasite that infests honey bees. The extensive use of acaricides, including fluvalinate, has led to the emergence of resistance in Varroa mite populations worldwide. This study's objective is to monitor fluvalinate resistance in field populations of Varroa mites in Korea through both bioassay-based and molecular marker-based methods. To achieve this, a residual contact vial (RCV) bioassay was established for on-site resistance monitoring. A diagnostic dose of 200 ppm was determined based on the bioassay using a putative susceptible population. In the RCV bioassay, early mortality evaluation was effective for accurately discriminating mites with the knockdown resistance (kdr) genotype, while late evaluation was useful for distinguishing mites with additional resistance factors. The RCV bioassay of 14 field mite populations collected in 2021 indicated potential resistance development in four populations. As an alternative approach, quantitative sequencing was employed to assess the frequency of the L925I/M mutation in the voltage-gated sodium channel (VGSC), associated with fluvalinate kdr trait. While the mutation was absent in 2020 Varroa mite populations, it emerged in 2021, increased in frequency in 2022, and became nearly widespread across the country by 2023. This recent emergence and rapid spread of fluvalinate resistance within a span of three years demonstrate the Varroa mite's significant potential for developing resistance. This situation further underscores the urgent need to replace fluvalinate with alternative acaricides. A few novel VGSC mutations potentially involved in resistance were identified. Potential factors driving the rapid expansion of resistance were further discussed.

RNAi turns 25:contributions and challenges in insect science.

Since its discovery in 1998, RNA interference (RNAi), a Nobel prize-winning technology, made significant contributions to advances in biology because of its ability to mediate the knockdown of specific target genes. RNAi applications in medicine and agriculture have been explored with mixed success. The past 25 years of research on RNAi resulted in advances in our understanding of the mechanisms of its action, target specificity, and differential efficiency among animals and plants. RNAi played a major role in advances in insect biology. Did RNAi technology fully meet insect pest and disease vector management expectations? This review will discuss recent advances in the mechanisms of RNAi and its contributions to insect science. The remaining challenges, including delivery to the target site, differential efficiency, potential resistance development and possible solutions for the widespread use of this technology in insect management.

Screening and Functional Analyses of Novel Cecropins from Insect Transcriptome.

Antibiotic resistance is a significant and growing threat to global public health. However, antimicrobial peptides (AMPs) have shown promise as they exhibit a broad spectrum of antibacterial activities with low potential for resistance development. Insects, which inhabit a wide range of environments and are incredibly diverse, remain largely unexplored as a source of novel AMPs. To address this, we conducted a screening of the representative transcriptomes from the 1000 Insect Transcriptome Evolution (1KITE) dataset, focusing on the homologous reference genes of Cecropins, the first identified AMPs in insects known for its high efficiency. Our analysis identified 108 Cecropin genes from 105 insect transcriptomes, covering all major hexapod lineages. We validated the gene sequences and synthesized mature peptides for three identified Cecropin genes. Through minimal inhibition concentration and agar diffusion assays, we confirmed that these peptides exhibited antimicrobial activities against Gram-negative bacteria. Similar to the known Cecropin, the three Cecropins adopted an alpha-helical conformation in membrane-like environments, efficiently disrupting bacterial membranes through permeabilization. Importantly, none of the three Cecropins demonstrated cytotoxicity in erythrocyte hemolysis tests, suggesting their safety in real-world applications. Overall, this newly developed methodology provides a high-throughput bioinformatic pipeline for the discovery of AMP, taking advantage of the expanding genomic resources available for diverse organisms.

Preparation and Antibacterial Properties of PLA-Based Composite Nanofiber Membrane Material Loaded with Cationic Antibacterial Agent by Electrospinning

With the continuous application of antibacterial materials, various problems have emerged, such as expensive prices and the potential development of resistance. Cationic antibacterial agents, due to their high solubility, reactivity, and antibacterial properties, are considered as environmentally friendly and cost-effective antibacterial agents. In addition, the electrospinning technique is recognized as a versatile and high-efficiency method to produce nanofibers with multifunctional properties and adjustable structures. In this work, we prepared a series of nanofiber membranes by electrospinning technology using hexadecyl trimethyl ammonium Bromide (CTAB) and 5-Chloro-8-hydroxyquinoline (5-Cl8Q) as antibacterial agents and polylactic acid (PLA) as substrate. The antimicrobial performance of PLA/CTAB/5-Cl8Q was the highest among the prepared materials, which inhabited S. aureus and E. coli up to 99.9% and 95.9%, respectively, and the antibacterial properties were stable. In general, PLA/CTAB/5-Cl8Q has great development potential, and it can be applied to real life as a cost-effective, biodegradable and highly antibacterial material.

Dual-Target Mycobacterium tuberculosis Inhibition: Insights into the Molecular Mechanism of Antifolate Drugs.

The escalating prevalence of drug-resistant strains of Mycobacterium tuberculosis has posed a significant challenge to global efforts in combating tuberculosis. To address this issue, innovative therapeutic strategies are required that target essential biochemical pathways while minimizing the potential for resistance development. The concept of dual targeting has gained prominence in drug discovery against resistance bacteria. Dual targeting recognizes the complexity of cellular processes and disrupts more than one vital pathway, simultaneously. By inhibiting more than one essential process required for bacterial growth and survival, the chances of developing resistance are substantially reduced. A previously reported study investigated the dual-targeting potential of a series of novel compounds against the folate pathway in Mycobacterium tuberculosis. Expanding on this study, we investigated the predictive pharmacokinetic profiling and the structural mechanism of inhibition of UCP1172, UCP1175, and UCP1063 on key enzymes, dihydrofolate reductase (DHFR) and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate reductase (RV2671), involved in the folate pathway. Our findings indicate that the compounds demonstrate lipophilic physiochemical properties that promote gastrointestinal absorption, and may also inhibit the drug-metabolizing enzyme, cytochrome P450 3A4, thus enhancing their biological half-life. Furthermore, key catalytic residues (Serine, Threonine, and Aspartate), conserved in both enzymes, were found to participate in vital molecular interactions with UCP1172, which demonstrated the most favorable free binding energies to both DHFR and RV2671 (-41.63 kcal/mol, -48.04 kcal/mol, respectively). The presence of characteristic loop shifts, which are similar in both enzymes, also indicates a common inhibitory mechanism by UCP1172. This elucidation advances the understanding of UCP1172's dual inhibition mechanism against Mycobacterium tuberculosis.

A small-molecule membrane fluidizer re-sensitizes methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics.

Novel antibacterial agents and strategies are urgently needed to fight against the ongoing global antibiotic resistance problem. While natural products remain the main source in antibiotic discovery, synthetic antibacterials provide an attractive alternative and may evade the ancient antibiotic resistance. Herein, we report a small molecule that re-sensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics with extremely low potential for resistance development. It belongs to a new class of broad-spectrum antibacterials, trypyricins, which share similar structural characteristics and mechanism of action to the cationic antimicrobial peptides. Mechanistic studies indicated that trypyricins fluidize and disrupt bacterial cytoplasmic membrane. These results suggested that trypyricins represent a promising new class of antibacterials and may be further developed as antibiotic adjuvants to fight against resistant bacteria in the clinic.

High-throughput phenotypic screen identifies a new family of potent anti-amoebic compounds.

Entamoeba histolytica is a disease-causing parasitic amoeba which affects an estimated 50 million people worldwide, particularly in socioeconomically vulnerable populations experiencing water sanitation issues. Infection with E. histolytica is referred to as amoebiasis, and can cause symptoms such as colitis, dysentery, and even death in extreme cases. Drugs exist that are capable of killing this parasite, but they are hampered by downsides such as significant adverse effects at therapeutic concentrations, issues with patient compliance, the need for additional drugs to kill the transmissible cyst stage, and potential development of resistance. Past screens of small and medium sized chemical libraries have yielded anti-amoebic candidates, thus rendering high-throughput screening a promising direction for new drug discovery in this area. In this study, we screened a curated 81,664 compound library from Janssen pharmaceuticals against E. histolytica trophozoites in vitro, and from it identified a highly potent new inhibitor compound. The best compound in this series, JNJ001, showed excellent inhibition activity against E. histolytica trophozoites with EC50 values at 0.29 μM, which is better than the current approved treatment, metronidazole. Further experimentation confirmed the activity of this compound, as well as that of several structurally related compounds, originating from both the Janssen Jump-stARter library, and from chemical vendors, thus highlighting a new structure-activity relationship (SAR). In addition, we confirmed that the compound inhibited E. histolytica survival as rapidly as the current standard of care and inhibited transmissible cysts of the related model organism Entamoeba invadens. Together these results constitute the discovery of a novel class of chemicals with favorable in vitro pharmacological properties. The discovery may lead to an improved therapy against this parasite and in all of its life stages.

Tinospora crispa Ethanolic Extract Downregulates Protein Kinase Genes Expression and Activity during Toxoplasma gondii Infection: A Prospective Drug Target for Lytic Cycle Inhibition

Infection with Toxoplasma gondii remains widespread among humans and animals as water, soil and food continue to serve as the major carriers of the sporulated oocyst. The infection is poorly controlled due to lack of a potent vaccine against the parasite, and the current medication presents severe side effects on the host, less efficacy on the parasite and is accompanied by the potential development of resistance by the parasite. The aim of this study was to evaluate the in vitro activities of ethanolic extract of Tinospora crispa (EETC) on protein kinases involved in the lytic cycle of T. gondii infection in Vero cell line. The EETC was obtained through the maceration of dried stem powder. Vero cells infected with the RH strain of T. gondii were used to evaluate the inhibitory effect of EETC against T. gondii calcium dependent protein kinase (CDPK) genes and microneme proteins (MIC) that are essential for host cell invasion and intracellular replication of the tachyzoite. Gene expression profiling of CDPK genes was determined through quantitative real-time PCR (qPCR) after 24 h of treatment. The expression of microneme protein was determined through western blot technique. The RT-qPCR revealed downregulation of most protein kinase (PK) genes after treatment with EETC. The expression of CDPK1, PKG, CDPK3, CDPK6, CDPK7 genes that participate in the lytic cycle of T. gondii infection was downregulated. The expression of the TgMIC1 and TgMIC2 proteins were observed to have decreased in both 4 and 24 h post-infection treatment models. This study showed that EETC contains promising drug candidates effective against T. gondii that can target the protein kinase genes involved in the lytic cycle of the parasite to prevent disease progression. HIGHLIGHTS This study explored the possible mechanism of action of phytochemicals on Toxoplasma gondii parasite-host cell invasion and intracellular replication The study evaluated the effects of ethanolic extract of Tinospora crispa Miers on protein kinase genes that are involved in host cell invasion The target protein kinase genes were downregulated which prevents the secretion of microneme proteins Inhibition of microneme secretion prevents host cell invasion and intracellular replication by Toxoplasma gondi GRAPHICAL ABSTRACT

The Lysin Exebacase Has a Low Propensity for Resistance Development in Staphylococcus aureus and Suppresses the Emergence of Resistance to Antistaphylococcal Antibiotics.

Exebacase (CF-301) belongs to a novel class of protein-based antibacterial agents, called lysins (peptidoglycan hydrolases). Exebacase exhibits potent antistaphylococcal activity and is the first lysin to initiate clinical trials in the United States. To support clinical development, the potential for resistance development to exebacase was assessed over 28 days of serial daily subculture in the presence of increasing concentrations of the lysin performed in its reference broth medium. Exebacase MICs remained unchanged over serial subculture for three replicates each of methicillin-susceptible Staphylococcus aureus (MSSA) strain ATCC 29213 and methicillin-resistant S. aureus (MRSA) strain MW2. For comparator antibiotics also tested, oxacillin MICs increased by 32-fold with ATCC 29213 and daptomycin and vancomycin MICs increased by 16- and 8-fold, respectively, with MW2. Serial passage was also used to examine the capacity of exebacase to suppress selection for increased oxacillin, daptomycin, and vancomycin MICs when used together in combination, wherein daily exposures to increasing concentrations of antibiotic were performed over 28 days with the added presence of fixed sub-MIC amounts of exebacase. Exebacase suppressed increases in antibiotic MICs over this period. These findings are consistent with a low propensity for resistance to exebacase and an added benefit of reducing the potential for development of antibiotic resistance. IMPORTANCE To guide development of an investigational new antibacterial drug, microbiological data are required to understand the potential for development of resistance to the drug in the target organism(s). Exebacase is a lysin (peptidoglycan hydrolase) that represents a novel antimicrobial modality based on degradation of the cell wall of Staphylococcus aureus. Exebacase resistance was examined here using an in vitro serial passage method that assesses the impact of daily exposures to increasing concentrations of exebacase over 28 days in medium approved for use in exebacase antimicrobial susceptibility testing (AST) by the Clinical and Laboratory Standards Institute (CLSI). No changes in susceptibility to exebacase were observed over the 28-day period for multiple replicates of two S. aureus strains, indicating a low propensity for resistance development. Interestingly, while high-level resistance to commonly used antistaphylococcal antibiotics was readily obtained using the same method, the added presence of exebacase acted to suppress antibiotic resistance development.

CRISPR-based genetic control strategies for insect pests

Genetic control strategies such as the sterile insect technique have successfully fought insect pests worldwide. The CRISPR (clustered regularly interspaced short palindromic repeats) technology, together with high-quality genomic resources obtained in more and more species, greatly facilitates the development of novel genetic control insect strains that can be used in area-wide and species-specific pest control programs. Here, we review the research progress towards state-of-art CRISPR-based genetic control strategies, including gene drive, sex ratio distortion, CRISPR-engineered genetic sexing strains, and precision-guided sterile insect technique. These strategies' working mechanisms, potential resistance development mechanisms, and regulations are illustrated and discussed. In addition, recent developments such as stacked and conditional systems are introduced. We envision that the advances in genetic technology will continue to be one of the driving forces for developing the next generation of pest control strategies.

Review Cannabis: A new strategy against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a global health concern. Many antibiotics are no longer effective at treating MRSA, which causes an increase in adverse patient outcomes. This has led to calls for new antibiotics and treatment strategies to combat the spread of MRSA and multidrug resistance (MDR). The antimicrobial secondary metabolites found in plants are a promising source for new antibiotics and treatment strategies. Cannabis sativa L. is especially promising, as it produces dozens of antimicrobial secondary metabolites that are active against Staphylococcus aureus (S. aureus) and MRSA strains. In addition to its antimicrobial properties against S. aureus and MRSA, cannabis has many other desirable properties for potential antibiotics. Cannabis secondary metabolites are active against a wide range of microorganisms, are generally safe, target multiple bacterial processes and structures, have antimicrobial synergies, have a low potential for resistance development, can be produced inexpensively and combined with existing antibiotics to further reduce costs, and contain secondary metabolites capable of penetrating a variety of in vivo environments. These characteristics make cannabis a potential resource against MRSA and MDR bacteria.

Improving Pennsylvania Bittercress Weed Control Efficacy with Mulch and Herbicide in Containers

Pennsylvania bittercress (Cardamine pensylvanica) and other bittercress (Cardamine) species are among the most common and difficult-to-control weed species in container nurseries, and they have been vouched in most counties in Florida. Preemergence herbicides can provide control, but concerns over potential resistance development, environmental issues, and crop injury problems associated with herbicide use create the need for alternative weed control methods to be explored. Previous studies have shown the potential of mulch materials for controlling weeds in nurseries, but their use along with preemergence herbicides has not been extensively investigated. To compare the effects of different mulch materials and herbicides on Pennsylvania bittercress control, a full factorial designed greenhouse study was conducted. Three mulch treatments including no mulch, pine (Pinus sp.) bark, and rice (Oryza sativa) hulls were evaluated with three herbicide treatments, including water (i.e., no herbicide), isoxaben, and prodiamine applied at label rates. Twenty-five seeds of Pennsylvania bittercress were sown on the surface of each container and emergence (percent), coverage (square centimeters), seedhead number, and biomass (grams) were measured. The results showed that Pennsylvania bittercress in containers mulched with rice hulls had the lowest emergence throughout the experiment. For coverage, seedhead, and biomass parameters, Pennsylvania bittercress seeded in rice hulls treatments had significantly lower coverage, fewer seedheads, and lower biomass compared with those in nonmulched or pine bark treatments, regardless of herbicide treatment. With isoxaben and the water check, nonmulched treatments had the highest coverage/seedhead/biomass, whereas with prodiamine, Pennsylvania bittercress in pine bark mulched containers had the highest coverage/seedhead/biomass. In conclusion, applying rice hulls alone can provide better Pennsylvania bittercress control compared with isoxaben or prodiamine applied alone.

In vitro and in vivo activities of a novel β-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China

XNW4107 is a novel β-lactamase inhibitor that possesses broad activity against serine-β-lactamases. XNW4107 in combination with imipenem exhibited potent in vitro activity against carbapenem-resistant bacteria and particularly against carbapenem-resistant Acinetobacter baumannii. This study aimed to evaluate the in vitro and in vivo antibacterial activities of imipenem/XNW4107. The minimum inhibitory concentrations, minimum bactericidal concentrations, time-kill curves, post-antibiotic effects, and spontaneous frequency of resistance were used to investigate the imipenem/XNW4107 in vitro activity. A mouse systemic infection model was used to evaluate the imipenem/XNW4107 in vivo efficacy. MIC90 of imipenem/XNW4107 against imipenem-nonsusceptible A. baumannii (n=106) was 8 mg/L, which was 16-fold lower than the MIC90 of imipenem; the resistance rate decreased from 90% to 20% applying the CLSI imipenem breakpoint. MIC90 of imipenem/XNW4107 against imipenem-resistant Klebsiella pneumoniae (n=54) was 2 mg/L, which was 128-fold lower than the MIC90 of imipenem; 80% imipenem-nonsusceptible Pseudomonas aeruginosa (n=101) exhibited MICs of imipenem/XNW4107 from 2 to 8 mg/L, which were 4- to 8-fold lower than the MICs of imipenem. Imipenem/XNW4107 was bactericidal against A. baumannii, K. pneumoniae, and Escherichia coli. The time-kill curves showed that increasing concentrations did not result in progressively increased killing at concentrations >4×MIC. Imipenem/XNW4107 has a low potential for resistance development in tested strains except for K. pneumoniae. Imipenem/XNW4107 provided good protection against imipenem-resistant A. baumannii and K. pneumoniae in vivo. The broad-spectrum profile and potent in vitro and in vivo antibacterial activities support imipenem/XNW4107 as a promising investigational candidate.

State of knowledge and challenges in the control and eradication of Onchocerciasis in Africa: a mini scoping review

Background: Onchocerciasis is a vector-borne neglected tropical disease (NTD) caused by the filarial worm Onchocerca volvulus. Given the high morbidity and mortality, onchocerciasis control gained great attention from many stakeholders both nationally and internationally. However, there are still the need for further solidified commitments and compelling initiatives across concerned stakeholders including regional bodies in the fight toward controlling its burden and risks. Thus, this review briefly appraised the current understanding and dynamics in the control and eradication efforts of Onchocerciasis in Africa. Methods: A rapid scoping review was used for this paper. Key databases used for this study include Web of Science, Scopus, Science Direct, PubMed and Google Scholar to identify a series of relevant peer-reviewed publications. The search contained just English-language articles. In addition, African government websites and specialized organizations such as WHO, UNAIDS, CDC, etc. were accessed and reviewed to gather important data on national and international control programs, related documentation and consultative expert reports. Results: In Africa, long-standing strides toward the control and elimination measures for onchocerciasis were conducted for several decades. Between 1974 to 2002, OCP had actively led the control and containment efforts for onchocerciasis in the context of 11 West Africa. However, endemic regions and states have switched their policies from controlling to eradication, with the ultimate objective of preventing their territories from parasite spread. Some key challenges are the insufficient identification of all endemic areas, high prevalence of both onchocerciasis and loiasis, potential development of resistance to ivermectin, inconsistent initiatives to address cross-border problems, disagreements and social disturbance. Various challenges, however, impede current efforts to eradicate African onchocerciasis. Conclusion: In the last decades, extensive measures have been taken with specialized state programs, largely efficient in high endemic nations, to manage and control onchocerciasis in African regions. The implications of these and other difficulties at country level control programs must therefore be identified and country-specific contextual remedies used to expedite the elimination of onchocerciasis.

Assessment of sustained efficacy and resistance emergence under human-simulated exposure of cefiderocol against Acinetobacter baumannii using in vitro chemostat and in vivo murine infection models.

ObjectivesThis study evaluated the sustained kill and potential for resistance development of Acinetobacter baumannii exposed to human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models.MethodsSeven A. baumannii isolates with cefiderocol MICs of 0.12–2 mg/L were tested. The sustained bactericidal activity compared with the initial inoculum and the resistance appearance over 72 h treatment were evaluated in both an in vitro chemostat and an in vivo murine thigh infection model under the human-simulated exposure of cefiderocol (2 g every 8 h as 3 h infusion).ResultsIn the in vitro model, regrowth was observed against all seven tested isolates and resistance emergence (>2 dilution MIC increase) was observed in five test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed in six of seven tested isolates in vivo. The mechanism of one resistant isolate that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. The resistance acquisition mechanisms of other isolates have not been identified.ConclusionsThe discrepancy in the sustained efficacy and resistance emergence between in vitro and in vivo models was observed for A. baumannii. Although the resistance mechanisms in vitro have not been fully identified, sustained efficacy without resistance emergence was observed in vivo for six of seven isolates. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among A. baumannii evaluated under human-simulated exposures.