Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination.

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Large scale changes in host methylation patterns induced by IncA/C plasmid transformation inVibrio cholerae

10.1101/399964 ◽

2018 ◽

Author(s):

Ruibai Wang ◽

Kanglin Wan

Keyword(s):

Drug Resistance ◽

Host Range ◽

Vibrio Cholerae ◽

Horizontal Transfer ◽

Large Scale ◽

Epigenetic Modification ◽

Bacterial Species ◽

Multi Drug Resistance ◽

Broad Host Range ◽

Methylation Patterns

AbstractDNA methylation is a central epigenetic modification and has diverse biological functions in eukaryotic and prokaryotic organisms alike. The IncA/C plasmid genomes are approximately 150kb in length and harbour three methylase genes, two of which demonstrate cytosine specificity. Transformation of theVibrio choleraestrain C6706 with the IncA/C plasmid pVC211 resulted in a significant relabelling of the methylation patterns on the host chromosomes. The new methylation patterns induced by transformation with IncA/C plasmid were accepted by the restriction enzymes of the host’s restriction modification (RM) system. These data uncover a novel mechanism by which plasmids can be compatible with a host’s RM system and suggest a possible reason that plasmids of the IncA/C family are broad-host-range.Author summaryAntibiotic resistance of bacteria is a growing serious problem worldwidely and the horizontal transfer of multi-drug resistance genes mediated by plasmids within and between species of bacteria is the main reason. In the researches of multi-drug resistance ofVibrio cholerae, I have isolated several IncA/C plasmids. What impressed me most is their ability to accumulate the resistant genes. Moreover, they can transfer with high frequency and are stable in several bacterial species. There are at least three Tra regions on the IncA/C plasmid which containing components of the Type 4 Secretion System and are important for conjugative transfer of plasmids. So the horizontal transfer ability of IncA/C plasmids is reasonable. There are three methylase genes on the small genome of IncA/C plasmids, which demonstrate cytosine specificity and are seldom in bacteria. Their modification target and roles are interesting. Here, we analysed the methylation profiles of the hostV. choeraeinduced by the plasmid pVC211 and found that they were completely changed. In addition to replicons, this may be a novel mechanism that plasmid cross the barrier of the host’s RM system and become broad-host range. Changing the activity of methylase in IncA/C plasmids may be a new way to affect the stability of IncA/C plasmids to eliminate these multidrug-resistant plasmids from bacteria.

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Fixing the ecosystem: Conservation, crisis and capital in Rwanda's Gishwati Forest

Environment and Planning E Nature and Space ◽

10.1177/2514848619826576 ◽

2019 ◽

Vol 2 (1) ◽

pp. 23-46 ◽

Cited By ~ 1

Author(s):

Nathan Clay

Keyword(s):

Large Scale ◽

Ecosystem Approach ◽

Agrarian Change ◽

Development Projects ◽

Landscape Modification ◽

Form And Function ◽

The Past ◽

Hybrid Spaces ◽

Social Environmental ◽

And Function

Conservation-development projects are increasingly enacted across large expanses of land where human livelihoods hang in the balance. Recent initiatives–often called ‘landscape approaches’ or ‘ecosystem-based’ conservation–aim to achieve economic development and conservation goals through managing hybrid spaces. I argue that the landscape/ecosystem approach is a socioecological fix: an effort to resolve social-environmental crises through sinking capital (financial, natural, and social) into an imagined ecosystem. Rwanda’s Gishwati Forest has been the locus of diverse crises and fixes over the past 40 years, including an industrial forestry and dairy project, a refugee settlement, a privately managed chimpanzee sanctuary, a carbon sequestration platform, and, most recently, an “integrated silvo-pastoral conservation landscape.” This paper considers how these governance schemes have intersected with broader processes of agrarian change to generate crises that subsequent conservation/development projects then attempt to resolve. I demonstrate how visions for ecosystems privilege certain forms of governance around which imagined socioecological histories are mobilized to frame problems and legitimize certain solutions, technologies, and actors. The Gishwati ecosystem and its fixes are repeatedly defined through an imaginary of crisis and degradation that engenders large-scale landscape modification while foreclosing reflection about root causes of crises or how these might be addressed. Thus, even while conservation/development paradigms have shifted over the past 40 years (from separating people and nature to integrating them in conservation landscapes), this crisis-fix metabolism has consistently generated livelihood insecurity for the tens of thousands of people living in and around Gishwati. Imagining and enacting more just and inclusive social-environmental landscapes will require making space for diverse voices to define ecosystem form and function as well as addressing deeply rooted power imbalances that are at the heart of recurrent crises.

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En-route to the ‘elimination’ of genotypic chloroquine resistance in Western and Southern Zambia, 14 years after chloroquine withdrawal

Malaria Journal ◽

10.1186/s12936-019-3031-4 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 2

Author(s):

Lungowe Sitali ◽

Mulenga C. Mwenda ◽

John M. Miller ◽

Daniel J. Bridges ◽

Moonga B. Hawela ◽

...

Keyword(s):

Drug Resistance ◽

Malaria Elimination ◽

Household Survey ◽

Chloroquine Resistance ◽

Multi Drug Resistance ◽

High Resolution Melt ◽

Cross Sectional ◽

Chloroquine Resistance Transporter ◽

Significant Difference ◽

Elimination Programme

Abstract Background Anti-malarial resistance is, and continues to be a significant challenge in the fight against malaria and a threat to achieving malaria elimination. In Zambia, chloroquine (CQ), a safe, affordable and well-tolerated drug, was removed from use in 2003 due to high levels of resistance evidenced with treatment failure. This study sought to investigate the prevalence of chloroquine resistance markers in Southern and Western Provinces of Zambia 14 years after the withdrawal of CQ. Methods Data from a cross-sectional, all-age household survey, conducted during the peak malaria transmission season (April–May 2017) was analysed. During the all-age survey, socio-demographic information and coverage of malaria interventions were collected. Consenting individuals were tested for malaria with a rapid diagnostic test and a spot of blood collected on filter paper to create a dried blood spot (DBS). Photo-induced electronic transfer–polymerase chain reaction (PET–PCR) was used to analyse the DBS for the presence of all four malaria species. Plasmodium falciparum positive samples were analysed by high resolution melt (HRM) PCR to detect the presence of genotypic markers of drug resistance in the P. falciparum chloroquine resistance transporter (Pfcrt) and P. falciparum multi-drug resistance (Pfmdr) genes. Results A total of 181 P. falciparum positive samples were examined for pfcrt K76T and MDR N86. Of the 181 samples 155 successfully amplified for Pfcrt and 145 for Pfmdr N86. The overall prevalence of CQ drug-resistant parasites was 1.9% (3/155), with no significant difference between the two provinces. No N86Y/F mutations in the Pfmdr gene were observed in any of the sample. Conclusion This study reveals the return of CQ sensitive parasites in Southern and Western Provinces of Zambia 14 years after its withdrawal. Surveillance of molecular resistant markers for anti-malarials should be included in the Malaria Elimination Programme so that resistance is monitored country wide.

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Violence and Discrimination Among Ugandan Residents During the COVID-19 Lockdown

10.21203/rs.3.rs-79334/v1 ◽

2020 ◽

Author(s):

Elizabeth Katana ◽

Bob Omoda Amodan ◽

Lilian Bulage ◽

Alex R. Ario ◽

Joseph Nelson Siewe Fodjo ◽

...

Keyword(s):

Public Health ◽

Law Enforcement ◽

Large Scale ◽

Control Measures ◽

Sub Saharan Africa ◽

World Health ◽

Transport Systems ◽

Outcome Variable ◽

Factors Associated ◽

The Past

Abstract Background: In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic. Many countries in Sub Saharan Africa, Uganda inclusive, implemented lockdowns, curfew, banning of both private and public transport systems and mass gatherings to minimize spread. Media reports indicated that cases of violence and discrimination had increased in Uganda’s communities following the lockdown. We estimated the incidence and factors associated with experiencing violence and discrimination among Ugandans during the COVID-19 lockdown to inform control and prevention measures.Methods: In April 2020, we conducted a cross-sectional study under the International Citizen Project (ICP) to assess adherence to public health measures and their impact on the COVID-19 outbreak in Uganda. We abstracted and analyzed data on violence and discrimination from the ICP study. We performed descriptive statistics for all the participants’ characteristics and created a binary outcome variable called experiencing violence and/or discrimination. We performed logistic regression analysis to identify the factors associated with experiencing violence and discrimination.Results: Of the 1,726 ICP study participants, 1,051 (58.8%) were males, 841 (48.7%) were currently living with a spouse or partner, and 376 (21.8%) had physically attended work for more than 3 days in the past week. Overall, 145 (8.4%) experienced any form of violence and/or discrimination by any perpetrator, and 46 (31.7%) of the 145 reported that it was perpetrated by a law enforcement officer. Factors associated with experiencing violence or discrimination were: being male (AOR= 1.60 CI:1.10-2.33), having attended work physically for more than 3 days in the past week (AOR=1.52 CI:1.03-2.23), and inability to access social or essential health services since the epidemic started (AOR=3.10 CI:2.14-4.50).Conclusion: A substantial proportion of Ugandan residents experienced violence and/or discrimination during the COVID-19 lockdown, mostly perpetrated by law enforcement officers. Mitigation of violence and/or discrimination, as well as increased access to health and social services should be integrated into control measures in large-scale public health emergencies.

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Prevalence and factors associated with HIV-1 multi-drug resistance over the past two decades in the Italian ARCA database

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2020.106252 ◽

2020 ◽

pp. 106252

Author(s):

Francesca Lombardi ◽

Andrea Giacomelli ◽

Daniele Armenia ◽

Alessia Lai ◽

Alex Dusina ◽

...

Keyword(s):

Drug Resistance ◽

Multi Drug Resistance ◽

Factors Associated ◽

The Past ◽

Hiv 1

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Emergence of Colistin Resistance against Multi-Drug Resistance Microorganisms and its Clinical Outcomes

10.53350/pjmhs2115102838 ◽

2021 ◽

Vol 15 (10) ◽

pp. 2838-2840

Author(s):

Ahmed F. Mady ◽

Basheer Abdulrahman ◽

Mohammad Al Odat ◽

Waqas Mahmood ◽

Saima Akhtar ◽

...

Keyword(s):

Drug Resistance ◽

Clinical Outcomes ◽

Length Of Hospital Stay ◽

Multidrug Resistant ◽

Multi Drug Resistance ◽

Positive Finding ◽

Colistin Resistance ◽

The Past ◽

Medical City ◽

Evolution Of Resistance

Background: Over the past decade, excessive use of Colistin against multidrug-resistant, Gram-negative bacteria have resulted in the evolution of resistance to Colistin. Objective: To evaluate efficacy of Colistin against multidrug-resistant organisms (MDRO), the emergence of Colistin resistance and its effects on clinical outcomes. Study Design: Retrospective study Place and Duration of Study: King Saud Medical City (KSMC) from 1st October 2015 till 31st January 2016. Methodology: Forty-three patients, resistant to Colistin on blood culture and sensitivity were enrolled. Results: Colistin was not effective at breaking the MDRO. The results revealed no significant impact of Colistin on site of infection such as chest, urinary tract or skin (p=0.612), types of organisms (p=0.629), length of hospital stay and the IV Colistin days (p=0.097 and p=0.166 respectively) in the past 12 months. The positive finding was that more than two third (76.7%) of the ICU patients were alive. Conclusion: Emergence of Multi drug resistance organism is matter of global concern that caused the ineffectiveness of many potent antibiotics and led to the drastic clinical outcomes. Collaboration between medical, paramedical, and administrative staff, with strict implementation of preventive protocol can slow down the velocity of microbial multidrug resistance. Keywords: Multi-drug resistant, Colistin, Outbreak, Intensive care unit, critically ill patients

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MicroRNAs are important regulators of drug resistance in colorectal cancer

Biological Chemistry ◽

10.1515/hsz-2016-0308 ◽

2017 ◽

Vol 398 (8) ◽

pp. 929-938 ◽

Cited By ~ 29

Author(s):

Yang Zhang ◽

Jing Wang

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Cancer Treatment ◽

Advanced Colorectal Cancer ◽

Therapeutic Targets ◽

Effective Therapy ◽

Limited Data ◽

Continuous Development ◽

The Past ◽

Underlying Mechanisms

Abstract Despite of continuous development of cancer treatment over the past decades, drug resistance is still one of the major hurdles of effective therapy for advanced colorectal cancer (CRC) worldwide and the understanding of its underlying mechanisms remains limited. Data which have emerged suggests that many microRNAs (miRNAs) may contribute to drug resistance in CRC. Major findings on miRNA functions in drug resistance of CRC are systemically reviewed here, with the goal of providing new updates to broaden our comprehension of its mechanisms and evidence to utilize miRNAs as potential therapeutic targets for CRC treatment.

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Association between Existence of Integrons and Multi-Drug Resistance in Acinetobacter Isolated from Patients in Southern Iran

Polish Journal of Microbiology ◽

10.33073/pjm-2011-023 ◽

2011 ◽

Vol 60 (2) ◽

pp. 163-168 ◽

Cited By ~ 10

Author(s):

SARA JAPONI ◽

AZIZ JAPONI ◽

SHOREH FARSHAD ◽

AHYA ABDI ALI ◽

MARZIEH JAMALIDOUST

Keyword(s):

Drug Resistance ◽

Inhibitory Concentration ◽

Test Method ◽

Control Measures ◽

Multi Drug Resistance ◽

Pcr Assay ◽

Class 1 ◽

Antibiotic Susceptibility Patterns ◽

Susceptibility Patterns

Nosocomial infections caused by multi-drug resistant Acinetobacter pose a serious problem in many countries. This study aimed at determining the antibiotic susceptibility patterns and prevalence of different classes of integrons in isolated Acinetobacter. In addition, the association between production of specific bands in PCR assay and magnitude of multi-drug resistance was investigated. In total, 88 Acinetobacter strains were isolated from patients from October 2008 through September 2009. The Minimal inhibitory concentration (MIC) of 12 antibiotics conventionally used in clinics against the isolates, was determined by E-test method. The existence of integron classes was investigated by PCR assay through the amplification of integrase genes. The most effective antibiotic against Acinetobacter was colistin with 97.7% activity, followed by imipenem (77.3%) and meropenem (72.7%). The presence ofintegron classes 1 and 2 in 47 (53.4%) isolates was confirme, However, no class 3 was detected. The proportion of class 1, compared with class 2, was high (47.7% vs. 3.4%). The association between multi-drug resistance to norfloxacin, ceftazidime, gentamicin, ciprofloxacin, cefepime and amikacin and the presence of integrons was statistically significant. However, the association was not remarkable in many of the isolates which exhibited resistance to the rest of antibiotics. This may imply that in addition to integrons, other resistance determinants such as transposon and plasmid may also contribute to resistance. To reduce the pressure on sensitive isolates, comprehensive control measures should be implemented. Furthermore, wise application of effective antibiotics could help alleviate the situation. Colistin is the most effective antibiotic in vitro against Acinetobacter.

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Muddled mechanisms: recent progress towards antimalarial target identification

F1000Research ◽

10.12688/f1000research.9477.1 ◽

2016 ◽

Vol 5 ◽

pp. 2514 ◽

Cited By ~ 3

Author(s):

Rachel L. Edwards ◽

Audrey R. Odom John

Keyword(s):

High Throughput Screening ◽

Target Identification ◽

Control Measures ◽

Combination Therapies ◽

The Past ◽

Infection Control Measures ◽

Causative Agents ◽

The Impact ◽

Innovative Techniques ◽

Potential Public Health

In the past decade, malaria rates have plummeted as a result of aggressive infection control measures and the adoption of artemisinin-based combination therapies (ACTs). However, a potential crisis looms ahead. Treatment failures to standard antimalarial regimens have been reported in Southeast Asia, and devastating consequences are expected if resistance spreads to the African continent. To prevent a potential public health emergency, the antimalarial arsenal must contain therapeutics with novel mechanisms of action (MOA). An impressive number of high-throughput screening (HTS) campaigns have since been launched, identifying thousands of compounds with activity against one of the causative agents of malaria, Plasmodium falciparum. Now begins the difficult task of target identification, for which studies are often tedious, labor intensive, and difficult to interpret. In this review, we highlight approaches that have been instrumental in tackling the challenges of target assignment and elucidation of the MOA for hit compounds. Studies that apply these innovative techniques to antimalarial target identification are described, as well as the impact of the data in the field.

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Longitudinal Surveillance and Risk Assessment of Resistance in Escherichia coli to Enrofloxacin from a Large-Scale Chicken Farm in Hebei, China

Antibiotics ◽

10.3390/antibiotics10101222 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1222

Author(s):

Kaixuan Guo ◽

Yue Zhao ◽

Luqing Cui ◽

Zhengzheng Cao ◽

Fan Zhang ◽

...

Keyword(s):

Escherichia Coli ◽

Drug Resistance ◽

Large Scale ◽

Bacterial Resistance ◽

Rank Correlation ◽

Resistance Rate ◽

Multi Drug Resistance ◽

E Coli ◽

Microdilution Method ◽

Broth Microdilution Method

The purpose of this study was to investigate the changes of resistance phenotype and plasmid-mediated quinolone resistance genes (PMQRs) in Escherichia coli (E. coli) during enrofloxacin (ENR) administration in different breeding cycles. In 2020, 983 strains of E. coli were isolated from different samples in different cycles at the broiler farm with the largest single batch of slaughter capacity in Hebei Province, China. All samples were from chicken, environmental, and human sources. The sensitivity of the isolates to various antibiotics was determined by broth microdilution method. The findings of this study include: (1) the total isolation rate of E. coli in the four cycles was 63.83% (983/1540); (2) the average resistance rate of E. coli from 1-day-old chickens to enrofloxacin was as high as 75% in each cycle, and with the use of enrofloxacin, the resistance rate of E. coli from chickens gradually increased to 100%; (3) 107 strains of E. coli randomly selected from different cycles and sources demonstrated the multi-drug resistance phenotypes. The highest resistance rate was doxycycline (100%), and the lowest was erythromycin (54.21%); (4) the detection rate of PMQRs of E. coli from chickens in different cycles were always higher than that from environmental and human. In particular, the PMQRs pollution rate of chicken seedlings in each cycle was generally higher than that of other links; (5) We used SPSS software to analyze the Kendall rank correlation of the experimental data. The resistance of E. coli isolated from this farm to ciprofloxacin (CIP) may increase along with the increase of resistance to enrofloxacin (Kendall’s tau-b = 0.190, p = 0.021). All these data highlight the serious problem of bacterial resistance in this farm. Therefore, it is urgent to provide guidance for the prevention and control of colibacillosis and drug resistance in this farm.

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