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Emerging threat of antimicrobial resistance in Neisseria gonorrhoeae: pathogenesis, treatment challenges, and potential for vaccine development

Omeershffudin UNM, Kumar S

Arch Microbiol, 2023 Sep 09;205(10):330.
PMID: 37688619 DOI: 10.1007/s00203-023-03663-0

The continuous rise of antimicrobial resistance (AMR) is a serious concern as it endangers the effectiveness of healthcare interventions that rely on antibiotics in the long run. The increasing resistance of Neisseria gonorrhoeae, the bacteria responsible for causing gonorrhea, to commonly used antimicrobial drugs, is a major concern. This has now become a critical global health crisis. In the coming years, there is a risk of a hidden epidemic caused by the emergence of gonococcal AMR. This will worsen the global situation. Infections caused by N. gonorrhoeae were once considered easily treatable. However, over time, they have become increasingly resistant to commonly used therapeutic medications, such as penicillin, ciprofloxacin, and azithromycin. As a result, this pathogen is developing into a true "superbug," which means that ceftriaxone is now the only available option for initial empirical treatment. Effective management strategies are urgently needed to prevent severe consequences, such as infertility and pelvic inflammatory disease, which can result from delayed intervention. This review provides a thorough analysis of the escalating problem of N. gonorrhoeae, including its pathogenesis, current treatment options, the emergence of drug-resistant mechanisms, and the potential for vaccine development. We aim to provide valuable insights for healthcare practitioners, policymakers, and researchers in their efforts to combat N. gonorrhoeae antibiotic resistance by elucidating the multifaceted aspects of this global challenge.

Matched MeSH terms: Drug Resistance, Bacterial
Fulltext Acinetobacter spp. infections in Malaysia: a review of antimicrobial resistance trends, mechanisms and epidemiology

Mohd Rani F, A Rahman NI, Ismail S, Alattraqchi AG, Cleary DW, Clarke SC, et al.

Front Microbiol, 2017;8:2479.
PMID: 29312188 DOI: 10.3389/fmicb.2017.02479

Acinetobacter spp. are important nosocomial pathogens, in particular the Acinetobacter baumannii-calcoaceticus complex, which have become a global public health threat due to increasing resistance to carbapenems and almost all other antimicrobial compounds. High rates of resistance have been reported among countries in Southeast Asia, including Malaysia. In this review, we examine the antimicrobial resistance profiles of Acinetobacter spp. hospital isolates from Malaysia over a period of nearly three decades (1987-2016) with data obtained from various peer-reviewed publications as well as the Malaysian National Surveillance on Antibiotic Resistance (NSAR). NSAR data indicated that for most antimicrobial compounds, including carbapenems, the peak resistance rates were reached around 2008-2009 and thereafter, rates have remained fairly constant (e.g., 50-60% for carbapenems). Individual reports from various hospitals in Peninsular Malaysia do not always reflect the nationwide resistance rates and often showed higher rates of resistance. We also reviewed the epidemiology and mechanisms of resistance that have been investigated in Malaysian Acinetobacter spp. isolates, particularly carbapenem resistance and found that blaOXA-23 is the most prevalent acquired carbapenemase-encoding gene. From the very few published reports and whole genome sequences that are available, most of the Acinetobacter spp. isolates from Malaysia belonged to the Global Clone 2 (GC2) CC92 group with ST195 being the predominant sequence type. The quality of data and analysis in the national surveillance reports could be improved and more molecular epidemiology and genomics studies need to be carried out for further in-depth understanding of Malaysian Acinetobacter spp. isolates.

Matched MeSH terms: Drug Resistance, Bacterial*
Fulltext Point-of-Care for Evaluating Antimicrobial Resistance through the Adoption of Functional Materials

Singh S, Numan A, Cinti S

Anal Chem, 2022 Jan 11;94(1):26-40.
PMID: 34802244 DOI: 10.1021/acs.analchem.1c03856
Matched MeSH terms: Drug Resistance, Bacterial*
Fulltext Educational resource for antimicrobial resistance and stewardship for dentistry programmes: a research protocol

Ang CY, Dhaliwal JS, Muharram SH, Akkawi ME, Hussain Z, Rahman H, et al.

BMJ Open, 2021 07 07;11(7):e048609.
PMID: 34233993 DOI: 10.1136/bmjopen-2021-048609

INTRODUCTION: Antimicrobial resistance (AMR) is a global public and patient safety issue. With the high AMR risk, ensuring that the next generation of dentists that have optimal knowledge and confidence in the area of AMR is crucial. A systematic approach is vital to design an AMR content that is comprehensive and clinically relevant. The primary objective of this research study will be to implement a consensus-based approach to elucidate AMR content and curriculum priorities for professional dentistry programmes. This research aims to establish consensus along with eliciting opinion on appropriate AMR topics to be covered in the Bachelor of Dental Surgery syllabus.
METHODS AND ANALYSIS: A three-phase approach to validate content for curriculum guidelines on AMR will be adopted. First, literature review and content analysis were conducted to find out the available pertinent literature in dentistry programmes. A total of 23 potential literature have been chosen for inclusion within this study following literature review and analysis in phase 1. The materials found will be used to draft curriculum on antimicrobials for dentistry programmes. The next phase involves the validation of the drafted curriculum content by recruiting local and foreign experts via a survey questionnaire. Finally, Delphi technique will be conducted to obtain consensus on the important or controversial modifications to the revised curriculum.
ETHICS AND DISSEMINATION: An ethics application is currently under review with the Institute of Health Science Research Ethics Committee, Universiti Brunei Darussalam. All participants are required to provide a written consent form. Findings will be used to identify significant knowledge gaps on AMR aspect in a way that results in lasting change in clinical practice. Moreover, AMR content priorities related to dentistry clinical practice will be determined in order to develop need-based educational resource on microbes, hygiene and prudent antimicrobial use for dentistry programmes.

Matched MeSH terms: Drug Resistance, Bacterial
Modern vaccine development via reverse vaccinology to combat antimicrobial resistance

Tobuse AJ, Ang CW, Yeong KY

Life Sci, 2022 Aug 01;302:120660.
PMID: 35642852 DOI: 10.1016/j.lfs.2022.120660

With the continuous evolution of bacteria, the global antimicrobial resistance health threat is causing millions of deaths yearly. While depending on antibiotics as a primary treatment has its merits, there are no effective alternatives thus far in the pharmaceutical market against some drug-resistant bacteria. In recent years, vaccinology has become a key topic in scientific research. Combining with the growth of technology, vaccine research is seeing a new light where the process is made faster and more efficient. Although less discussed, bacterial vaccine is a feasible strategy to combat antimicrobial resistance. Some vaccines have shown promising results with good efficacy against numerous multidrug-resistant strains of bacteria. In this review, we aim to discuss the findings from studies utilizing reverse vaccinology for vaccine development against some multidrug-resistant bacteria, as well as provide a summary of multi-year bacterial vaccine studies in clinical trials. The advantages of reverse vaccinology in the generation of new bacterial vaccines are also highlighted. Meanwhile, the limitations and future prospects of bacterial vaccine concludes this review.

Matched MeSH terms: Drug Resistance, Bacterial
Fulltext Bacterial Persister Cells and Development of Antibiotic Resistance in Chronic Infections: An Update

Kunnath AP, Suodha Suoodh M, Chellappan DK, Chellian J, Palaniveloo K

Br J Biomed Sci, 2024;81:12958.
PMID: 39170669 DOI: 10.3389/bjbs.2024.12958

The global issue of antimicrobial resistance poses significant challenges to public health. The World Health Organization (WHO) has highlighted it as a major global health threat, causing an estimated 700,000 deaths worldwide. Understanding the multifaceted nature of antibiotic resistance is crucial for developing effective strategies. Several physiological and biochemical mechanisms are involved in the development of antibiotic resistance. Bacterial cells may escape the bactericidal actions of the drugs by entering a physiologically dormant state known as bacterial persistence. Recent findings in this field suggest that bacterial persistence can be one of the main sources of chronic infections. The antibiotic tolerance developed by the persister cells could tolerate high levels of antibiotics and may give rise to persister offspring. These persister offspring could be attributed to antibiotic resistance mechanisms, especially in chronic infections. This review attempts to shed light on persister-induced antibiotic resistance and the current therapeutic strategies.

Matched MeSH terms: Drug Resistance, Bacterial
Scope and applicability of social-ecological resilience to antimicrobial resistance

Wernli D, Søgaard Jørgensen P, Parmley EJ, Majowicz SE, Lambraki I, Carson CA, et al.

Lancet Planet Health, 2023 Jul;7(7):e630-e637.
PMID: 37438004 DOI: 10.1016/S2542-5196(23)00128-6

Social-ecological systems conceptualise how social human systems and ecological natural systems are intertwined. In this Personal View, we define the scope and applicability of social-ecological resilience to antimicrobial resistance. Resilience to antimicrobial resistance corresponds to the capacity to maintain the societal benefits of antimicrobial use and One Health systems' performance in the face of the evolutionary behaviour of microorganisms in response to antimicrobial use. Social-ecological resilience provides an appropriate framework to make sense of the disruptive impacts resulting from the emergence and spread of antimicrobial resistance; capture the diversity of strategies needed to tackle antimicrobial resistance and to live with it; understand the conditions that underpin the success or failure of interventions; and appreciate the need for adaptive and coevolutionary governance. Overall, resilience thinking is essential to improve understanding of how human societies dynamically can cope with, adapt, and transform to the growing global challenge of antimicrobial resistance.

Matched MeSH terms: Drug Resistance, Bacterial*
Fulltext A prospective study of tuberculosis drug susceptibility in Sabah, Malaysia, and an algorithm for management of isoniazid resistance

Rashid Ali MR, Parameswaran U, William T, Bird E, Wilkes CS, Lee WK, et al.

J Trop Med, 2015;2015:261925.
PMID: 25838829 DOI: 10.1155/2015/261925

Introduction. The burden of tuberculosis is high in eastern Malaysia, and rates of Mycobacterium tuberculosis drug resistance are poorly defined. Our objectives were to determine M. tuberculosis susceptibility and document management after receipt of susceptibility results.
Methods. Prospective study of adult outpatients with smear-positive pulmonary tuberculosis (PTB) in Sabah, Malaysia. Additionally, hospital clinicians accessed the reference laboratory for clinical purposes during the study.
Results. 176 outpatients were enrolled; 173 provided sputum samples. Mycobacterial culture yielded M. tuberculosis in 159 (91.9%) and nontuberculous Mycobacterium (NTM) in three (1.7%). Among outpatients there were no instances of multidrug resistant M. tuberculosis (MDR-TB). Seven people (4.5%) had isoniazid resistance (INH-R); all were switched to an appropriate second-line regimen for varying durations (4.5-9 months). Median delay to commencement of the second-line regimen was 13 weeks. Among 15 inpatients with suspected TB, 2 had multidrug resistant TB (one extensively drug resistant), 2 had INH-R, and 4 had NTM.
Conclusions. Current community rates of MDR-TB in Sabah are low. However, INH-resistance poses challenges, and NTM is an important differential diagnosis in this setting, where smear microscopy is the usual diagnostic modality. To address INH-R management issues in our setting, we propose an algorithm for the treatment of isoniazid-resistant PTB.
Study site: Tuberculosis clinic, Klinik Kesihatan Luyang, Kota Kinabalu, Sabah, Malaysia

Matched MeSH terms: Drug Resistance, Bacterial*
Fulltext Evidence for action: a One Health learning platform on interventions to tackle antimicrobial resistance

Wernli D, Jørgensen PS, Parmley EJ, Troell M, Majowicz S, Harbarth S, et al.

Lancet Infect Dis, 2020 Dec;20(12):e307-e311.
PMID: 32853549 DOI: 10.1016/S1473-3099(20)30392-3

Improving evidence for action is crucial to tackle antimicrobial resistance. The number of interventions for antimicrobial resistance is increasing but current research has major limitations in terms of efforts, methods, scope, quality, and reporting. Moving the agenda forwards requires an improved understanding of the diversity of interventions, their feasibility and cost-benefit, the implementation factors that shape and underpin their effectiveness, and the ways in which individual interventions might interact synergistically or antagonistically to influence actions against antimicrobial resistance in different contexts. Within the efforts to strengthen the global governance of antimicrobial resistance, we advocate for the creation of an international One Health platform for online learning. The platform will synthesise the evidence for actions on antimicrobial resistance into a fully accessible database; generate new scientific insights into the design, implementation, evaluation, and reporting of the broad range of interventions relevant to addressing antimicrobial resistance; and ultimately contribute to the goal of building societal resilience to this central challenge of the 21st century.

Matched MeSH terms: Drug Resistance, Bacterial*
Fulltext Diagnostic performance of Xpert MTB/RIF ultra in detecting Mycobacterium tuberculosis and Rifampicin Resistance in AFB Smear-negative Pulmonary and Extrapulmonary Tuberculosis samples in Malaysia

Noor AM, Ghazali SM, Bakar ZA, Ruzan IN

Diagn Microbiol Infect Dis, 2024 Jun;109(2):116230.
PMID: 38507965 DOI: 10.1016/j.diagmicrobio.2024.116230

Rapid and highly accurate diagnostic tools are critically needed to diagnose Mycobacterium tuberculosis and rifampicin resistance in AFB smear-negative samples. In this study, we evaluated the diagnostic performance of Xpert MTB/RIF Ultra (Ultra) as a rapid test to diagnose tuberculosis in smear-negative cases in Malaysia. A retrospective study of 1960 smear-negative pulmonary and extrapulmonary samples obtained from patients was conducted. Culture was used as the reference standard for the study. The overall sensitivity and specificity of Ultra on the tested samples were 88.7 % and 77.2 %, respectively, while the PPV was 32.3 % and the NPV was 98.2 %. Ultra showed slightly higher sensitivity in pulmonary (89.9 %) compared to extrapulmonary samples (86.1 %). The overall accuracy of Ultra was 78.5 % (kappa=0.37; 95 %CI: 0.32,0.42). Ultra showed good diagnostic accuracy for detecting MTB and rifampicin resistance in various AFB smear-negative samples. Ultra also had excellent capability in rifampicin resistance detection.

Matched MeSH terms: Drug Resistance, Bacterial*
Charting the global footprint of borderline oxacillin-resistant Staphylococcus aureus (BORSA): the first systematic review and meta-analysis

Engku Abd Rahman ENS, Irekeola AA, Yamin D, Elmi AH, Chan YY

PeerJ, 2024;12:e18604.
PMID: 39703916 DOI: 10.7717/peerj.18604

Borderline oxacillin-resistant Staphylococcus aureus (BORSA) has been a persistent yet under-researched concern in the realm of antibiotic resistance, characterized by unique resistance mechanisms and potential for severe infections. This systematic review and meta-analysis consolidates data from 29 studies encompassing 18,781 samples, revealing a global BORSA prevalence of 6.6% (95% CI [4.0-10.7]). The highest prevalence was found in animals (46.3%), followed by food (8.9%), and humans (5.1%). Notably, significant regional disparities were observed, with Brazil exhibiting the highest prevalence at 70.0%, while The Netherlands reported just 0.5%. These findings underscore the multifaceted nature of BORSA epidemiology, influenced by local antibiotic usage practices and healthcare infrastructures. The analysis also reveals substantial heterogeneity (I2 = 96.802%), highlighting the need for improved reporting practices and tailored surveillance protocols that account for the specific contexts of each study. As antibiotic resistance continues to escalate, understanding BORSA's global footprint is crucial for informing targeted interventions and optimizing antibiotic stewardship programs. This study fills critical gaps in current knowledge of BORSA and highlights the need for coordinated efforts among researchers, healthcare providers, and policymakers to develop effective strategies for addressing the rising threat of antibiotic-resistant pathogens like BORSA, including further exploration of its genetic and phenotypic characteristics.

Matched MeSH terms: Drug Resistance, Bacterial/drug effects
Fulltext Antimicrobial resistance: Prevalence, economic burden, mechanisms of resistance and strategies to overcome

Pulingam T, Parumasivam T, Gazzali AM, Sulaiman AM, Chee JY, Lakshmanan M, et al.

Eur J Pharm Sci, 2022 Mar 01;170:106103.
PMID: 34936936 DOI: 10.1016/j.ejps.2021.106103

Antibiotic resistance is a major health concern globally and has been estimated to cause 10 million deaths worldwide by year 2050 if the current trend of inappropriate and excessive use of antibiotics continues. Although, the discovery of antibiotics has saved countless of lives for the past 80 years, increasing levels of bacterial resistance to antibiotics would jeopardize the progress in clinical and agricultural sectors and may cause life-threatening situations even for previously treatable bacterial infections. Antibiotic resistance would increase the levels of poverty of low-middle income countries mostly due to extended hospital stays, higher cost of treatment and untimely deaths that directly affect the total productivity rate. Recent incidences of antibiotic resistance have been gradually increasing globally and this may potentiate horizontal transmission of the resistant gene and have been linked with cross-resistance to other antibiotic families as well. This review summarizes the global burden of antibiotic resistance from the economic viewpoint, highlights the recent incidences of antibiotic resistance mainly related to Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella spp. and Staphylococcus aureus, describes the common mechanistic actions of antibiotic resistance and potential strategies to overcome antibiotic resistance.

Matched MeSH terms: Drug Resistance, Bacterial
Fulltext Is scientific evidence enough? Using expert opinion to fill gaps in data in antimicrobial resistance research

Cousins M, Parmley EJ, Greer AL, Neiterman E, Lambraki IA, Graells T, et al.

PLoS One, 2023;18(8):e0290464.
PMID: 37616319 DOI: 10.1371/journal.pone.0290464

BACKGROUND: Antimicrobial Resistance (AMR) is a global problem with large health and economic consequences. Current gaps in quantitative data are a major limitation for creating models intended to simulate the drivers of AMR. As an intermediate step, expert knowledge and opinion could be utilized to fill gaps in knowledge for areas of the system where quantitative data does not yet exist or are hard to quantify. Therefore, the objective of this study was to identify quantifiable data about the current state of the factors that drive AMR and the strengths and directions of relationships between the factors from statements made by a group of experts from the One Health system that drives AMR development and transmission in a European context.
METHODS: This study builds upon previous work that developed a causal loop diagram of AMR using input from two workshops conducted in 2019 in Sweden with experts within the European food system context. A secondary analysis of the workshop transcripts was conducted to identify semi-quantitative data to parameterize drivers in a model of AMR.
MAIN FINDINGS: Participants spoke about AMR by combining their personal experiences with professional expertise within their fields. The analysis of participants' statements provided semi-quantitative data that can help inform a future of AMR emergence and transmission based on a causal loop diagram of AMR in a Swedish One Health system context.
CONCLUSION: Using transcripts of a workshop including participants with diverse expertise across the system that drives AMR, we gained invaluable insight into the past, current, and potential future states of the major drivers of AMR, particularly where quantitative data are lacking.

Matched MeSH terms: Drug Resistance, Bacterial
Epidemiological cut-off values for Vibrio parahaemolyticus calculated from minimal inhibitory concentration data generated at 35 and 28°C

Smith P, Joseph A, Baker-Austin C, Kang N, Baron S, Le Devendec L, et al.

Dis Aquat Organ, 2024 Dec 12;160:127-134.
PMID: 39665310 DOI: 10.3354/dao03831

This work was performed to generate the data needed to set epidemiological cut-off values for minimal inhibitory concentrations (MICs) of 10 antimicrobial agents against Vibrio parahaemolyticus determined using standardised broth microdilution protocols. Eight laboratories performed broth microdilution tests with incubation at 35°C for 16 to 20 h, and 7 also performed tests on the same isolates with incubation at 28°C for 24 to 28 h. Data were analysed by the ECOFFinder and normalised resistance interpretation algorithms. The cut-off values calculated for ceftazidime, florfenicol and trimethoprim/sulfamethoxazole, 1, 1 and 0.25/4.75 µg ml-1, respectively, were the same when calculated from data obtained at both temperatures. The cut-off values calculated from data obtained at 35°C and from data obtained at 28°C were 0.25 and 0.5 µg ml-1 for enrofloxacin, 2 and 4 µg ml-1 for gentamicin, 0.5 and 1 µg ml-1 for oxolinic acid and 2 and 1 µg ml-1 for oxytetracycline, respectively. The influence of incubation temperature on MIC values was investigated by comparing MICs obtained at 35 and 28°C for a specific antimicrobial agent with a particular isolate by an individual laboratory. Results showed that 56% of 1473 of these paired MIC values were identical, while 38% differed from one another by not more than 1 dilution step. The data generated in this work will be submitted to the Clinical and Laboratory Standards Institute for consideration in their setting of internationally agreed epidemiological cut-off values for V. parahaemolyticus that are essential for interpreting antimicrobial susceptibility testing data of this species.

Matched MeSH terms: Drug Resistance, Bacterial
Tolerance of the antibiotic tylosin on treatment performance of an up-flow anaerobic stage reactor (UASR)

Chelliapan S, Wilby T, Sallis PJ, Yuzir A

Water Sci Technol, 2011;63(8):1599-606.
PMID: 21866757

Tylosin has been considered inhibiting COD removal in anaerobic digestion. In this study it is proven that this is not always the case. Accordingly, elevated concentrations of Tylosin (100-800mgL-1) could be tolerated by the anaerobic system. The influence of Tylosin concentrations on an up-flow anaerobic stage reactor (UASR) was assessed using additions of Tylosin phosphate concentrate. Results showed high efficiency for COD removal (average 93%) when Tylosin was present at concentrations ranging from 0 to 400 mg L-1. However, at Tylosin concentrations of 600 and 800 mg L-1 treatment efficiency declined to 85% and 75% removal respectively. The impact of Tylosin concentrations on archaeal activity were investigated and the analysis revealed that archaeal cells dominated the reactor, confirming that there was no detectable inhibition of the methanogens at Tylosin levels between 100 and 400mg L-1. Nevertheless, the investigation showed a slight reduction in the number of methanogens at Tylosin levels of 600 and 800 mg L-1. These results demonstrated that the methanogens were well adapted to Tylosin. It would not be expected that the process performance of the UASR would be affected, not even at a level well in excess of those appearing in real wastewater from a Tylosin production site.

Matched MeSH terms: Drug Resistance, Bacterial*
Fulltext Profiling of Potential Antibacterial Compounds of Lactic Acid Bacteria against Extremely Drug Resistant (XDR) Acinetobacter baumannii

Yap PC, Ayuhan N, Woon JJ, Teh CSJ, Lee VS, Azman AS, et al.

Molecules, 2021 Mar 19;26(6).
PMID: 33808805 DOI: 10.3390/molecules26061727

A total of 20 of isolates of lactic acid bacteria (LAB) were selected and screened for antagonistic activity against clinical strains of 30 clinical isolates of extremely drug-resistant (XDR) Acinetobacter baumannii using the well diffusion assay method. Results showed that 50% of the highly LAB strains possessed inhibitory activity against (up to 66%) of the XDR A. baumannii strains tested. The supernatant of the twenty LAB strains was subjected to gas chromatography mass spectrometry (GCMS) revealed that the common compound found in the active isolates against XDR A. baumannii was 3-Isobutyl-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, a known potential diketopiperazine group. The molecular docking study against potential antibacterial targets with selected ligands was performed to predict the binding mode of interactions, which is responsible for antibacterial activity. The docking analysis of the potent compounds supported the potential antibacterial activity exhibiting high inhibition constant and binding affinity in silico.

Matched MeSH terms: Drug Resistance, Bacterial/drug effects*
Metabonomics reveals an alleviation of fitness cost in resistant E. coli competing against susceptible E. coli at sub-MIC doxycycline

Wen X, Cao J, Mi J, Huang J, Liang J, Wang Y, et al.

J Hazard Mater, 2021 03 05;405:124215.
PMID: 33109407 DOI: 10.1016/j.jhazmat.2020.124215

High concentrations of antibiotics may induce bacterial resistance mutations and further lead to fitness costs by reducing growth of resistant bacteria. However, antibiotic concentrations faced by bacteria are usually low in common environments, which leads to questions about how resistant bacteria with fitness costs regulate metabolism to coexist or compete with susceptible bacteria during sublethal challenge. Our study revealed that a low proportion (< 15%) of resistant bacteria coexisted with susceptible bacteria due to the fitness cost without doxycycline. However, the cost for the resistant strain decreased at a doxycycline concentration of 1 mg/L and even disappeared when the doxycycline concentration was 2 mg/L. Metabonomics analysis revealed that bypass carbon metabolism and biosynthesis of secondary metabolites were the primary metabolic pathways enriching various upregulated metabolites in resistant bacteria without doxycycline. Moreover, the alleviation of fitness cost for resistant bacteria competed with susceptible bacteria at 1 mg/L doxycycline was correlated with the downregulation of the biomarkers pyruvate and pilocarpine. Our study offered new insight into the metabolic mechanisms by which the fitness cost of resistant mutants was reduced at doxycycline concentrations as low as 1 mg/L and identified various potential metabolites to limit the spread of antimicrobial resistance in the environment.

Matched MeSH terms: Drug Resistance, Bacterial/genetics
A stop-gain mutation in sigma factor SigH (MAB_3543c) may be associated with tigecycline resistance in Mycobacteroides abscessus

Lee CL, Ng HF, Ngeow YF, Thaw Z

J Med Microbiol, 2021 Jul;70(7).
PMID: 34236301 DOI: 10.1099/jmm.0.001378

Introduction. Tigecycline is currently acknowledged to be one of the most effective antibiotics against infections caused by Mycobacteroides abscessus.Gap statement. The genetic determinants of tigecycline resistance in M. abscessus are not well understood.Aim. In this study, we characterized a tigecycline-resistant M. abscessus mutant, designated CL7, to identify the potential resistance mechanism.Methodology. CL7 was characterized using antimicrobial susceptibility testing, whole-genome sequencing, PCR and RT-qPCR. For biological verification, gene overexpression assays were carried out.Results. Whole-genome sequencing and the subsequent gene overexpression assays showed that CL7 harboured a stop-gain mutation in MAB_3543 c, which may be responsible for the tigecycline resistance phenotype. This gene encodes an orthologue of SigH, which is involved in the positive regulation of physiological stress response and is negatively regulated by the RshA anti-sigma factor in Mycobacterium tuberculosis. We hypothesized that the MAB_3543 c mutation may disrupt the interaction between SigH and RshA (MAB_3542 c). RT-qPCR analyses revealed the upregulation of MAB_3543 c and other key stress response genes, which has previously been shown to be a hallmark of SigH-RshA bond disruption and tigecycline resistance.Conclusion. The MAB_3543c mutation may represent a novel determinant of tigecycline resistance in M. abscessus. The findings of this study will hopefully contribute to our knowledge of potential tigecycline resistance mechanisms in M. abscessus, which may lead to better diagnostics and treatment modalities in the future.

Matched MeSH terms: Drug Resistance, Bacterial/genetics*
Fulltext The challenges of designing a benchmark strategy for bioinformatics pipelines in the identification of antimicrobial resistance determinants using next generation sequencing technologies

Angers-Loustau A, Petrillo M, Bengtsson-Palme J, Berendonk T, Blais B, Chan KG, et al.

F1000Res, 2018;7.
PMID: 30026930 DOI: 10.12688/f1000research.14509.2

Next-Generation Sequencing (NGS) technologies are expected to play a crucial role in the surveillance of infectious diseases, with their unprecedented capabilities for the characterisation of genetic information underlying the virulence and antimicrobial resistance (AMR) properties of microorganisms. In the implementation of any novel technology for regulatory purposes, important considerations such as harmonisation, validation and quality assurance need to be addressed. NGS technologies pose unique challenges in these regards, in part due to their reliance on bioinformatics for the processing and proper interpretation of the data produced. Well-designed benchmark resources are thus needed to evaluate, validate and ensure continued quality control over the bioinformatics component of the process. This concept was explored as part of a workshop on "Next-generation sequencing technologies and antimicrobial resistance" held October 4-5 2017. Challenges involved in the development of such a benchmark resource, with a specific focus on identifying the molecular determinants of AMR, were identified. For each of the challenges, sets of unsolved questions that will need to be tackled for them to be properly addressed were compiled. These take into consideration the requirement for monitoring of AMR bacteria in humans, animals, food and the environment, which is aligned with the principles of a "One Health" approach.

Matched MeSH terms: Drug Resistance, Bacterial/genetics*
Mutations in Genes Encoding 23S rRNA and FadD32 May be Associated with Linezolid Resistance in Mycobacteroides abscessus

Ng HF, Ngeow YF

Microb Drug Resist, 2023 Feb;29(2):41-46.
PMID: 36802272 DOI: 10.1089/mdr.2022.0068

Linezolid is one of the antibiotics used to treat the Mycobacteroides abscessus infection. However, linezolid-resistance mechanisms of this organism are not well understood. The objective of this study was to identify possible linezolid-resistance determinants in M. abscessus through characterization of step-wise mutants selected from a linezolid-susceptible strain, M61 (minimum inhibitory concentration [MIC]: 0.25 mg/L). Whole-genome sequencing and subsequent PCR verification of the resistant second-step mutant, A2a(1) (MIC: >256 mg/L), revealed three mutations in its genome, two of which were found in the 23S rDNA (g2244t and g2788t) and another one was found in a gene encoding the fatty-acid-CoA ligase FadD32 (c880t→H294Y). The 23S rRNA is the molecular target of linezolid and mutations in this gene are likely to contribute to resistance. Furthermore, PCR analysis revealed that the c880t mutation in the fadD32 gene first appeared in the first-step mutant, A2 (MIC: 1 mg/L). Complementation of the wild-type M61 with the pMV261 plasmid carrying the mutant fadD32 gene caused the previously sensitive M61 to develop a reduced susceptibility to linezolid (MIC: 1 mg/L). The findings of this study uncovered hitherto undescribed mechanisms of linezolid resistance in M. abscessus that may be useful for the development of novel anti-infective agents against this multidrug-resistant pathogen.

Matched MeSH terms: Drug Resistance, Bacterial/genetics

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