The Rising Threat of Antimicrobial Resistance

Posted on 2024-11-26

Overview

Antimicrobial resistance (AMR) presents one of the most pressing challenges to contemporary medicine and public health (1). It contributes up to 10 million deaths per year, which is expected to increase to up to 10 million deaths per year by 2050 (2). In recognition of its severe impact, the World Health Organisation (WHO) has listed AMR as one of the top ten global health threats, a qualification initially awarded in 2014, that remains the same 10 years later (3).

Following the discovery of penicillin by Alexander Fleming in 1928, antimicrobials have been widely used (4). As a result, selective pressure has been exerted on microorganisms, accelerating natural selection and leading to the rapid development of antibiotic-resistant bacteria (5). Consequently, less than ten years after the introduction of penicillin, the first reports of penicillin-resistant bacteria emerged (6). Over the following decades, as new classes of antibiotics were developed, resistance soon followed, highlighting the evolutionary dynamic between microbes and medicine (7). 

Mechanisms of Resistance

The WHO has identified several pathogens that pose significant threats to public health due to their resistance to antimicrobial treatments, including Staphylococcus aureus (MRSA), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and MDR Pseudomonas aeruginosa, which are classified as priority pathogens (5). Among these, gram-negative bacteria such as P. aeruginosa, are particularly concerning due to their inherent abilities to develop simultaneous mechanisms of resistance and transfer genetic material to other bacteria, leading to the spread of drug-resistant strains (8). 

In contrast, viruses primarily acquire resistance through mutations in the genetic material, which can alter the structure of viral proteins, such as enzymes or surface receptors, preventing drugs from binding to their target (9). Fungi mainly rely on efflux pumps to expel antifungal drugs, reducing their intracellular concentrations (10). Lastly, parasites adapt by a combination of mechanisms, including altering the metabolic pathways, which allows them to bypass the effects of antiparasitic drugs entirely (11). 

The following table provides a summary of the key mechanisms employed by different microorganisms to resist antimicrobial agents (Table 1).

Table 1: Mechanisms of Antimicrobial Resistance

Abbexa’s Research Highlight: “Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance” by Hasan et al.

Hasan et al. investigated the gram-negative bacterium P. aeruginosa, an opportunistic pathogen responsible for severe infections, including chronic respiratory infections in individuals with cystic fibrosis, pneumonia, and bloodstream infections in immunocompromised individuals (20). The study determined how P. aeruginosa leverages host-derived spermidine – a polyamine involved in a range of cellular processes – to enhance its resistance to antimicrobial drugs (21).

The researchers used Abbexa’s Spermidine ELISA kit (abx585001) to quantify spermidine levels in bacterial cultures, infected mouse lung tissues, and cystic fibrosis sputum samples. Bacterial supernatants were extracted from P. aeruginosa cultures and tissue homogenates from infected mice, which were then tested using our Spermidine ELISA kit (abx585001)(21). The Abbexa Spermidine ELISA kit enabled the detection of increased spermidine levels during infection, highlighting the bacterium’s adaptive mechanisms.

Key Findings

1. Bacterial Cultures: Elevated spermidine levels were observed in P. aeruginosa during infection. In PmrB-deficient strains, which have modified LPS, spermidine binding was enhanced.
2. Mouse Tissue: Increased spermidine levels in the lung and sinus tissues of infected mice were observed, correlating with antimicrobial treatment. 
3. CF Sputum: Higher spermidine concentrations were noted during treatment phases, suggesting its role in modulating resistance. 

Overall, the study demonstrated that P. aeruginosa scavenges spermidine from the host to modify its outer membrane, reducing antimicrobial efficacy, particularly against cationic peptides. These findings suggest that targeting spermidine interactions may help improve the effectiveness of current treatments, particularly against biofilm-forming pathogens (21). 

Other P. aeruginosa Products

To support ongoing research on P. aeruginosa and AMR, Abbexa offers a diverse range of products, including:

• Antibodies
• Serotype 3
• Serotype 6
• Serotype 9

Explore our full range of P. aeruginosa antibodies here.

• Protein
• Translational Activator LasR (lasR)
• Peptide
• CFTR (108-117)

Abbexa is committed to advancing AMR research by offering an extensive, results-driven catalogue of key products that support scientific progress. For research focused on other MDR pathogens, such as S. aureus and MDR-TB, our products are designed to support and drive progress in AMR solutions.

References

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2. Cosgrove SE, Carmeli Y. The Impact of Antimicrobial Resistance on Health and Economic Outcomes. Clinical Infectious Diseases [Internet]. 2003 Jun 1 [cited 2024 Nov 21];36(11):1433–7. Available from: https://dx.doi.org/10.1086/375081

3. Merlino J. Antimicrobial resistance a threat to public health. Microbiol Aust [Internet]. 2017 Nov 28 [cited 2024 Nov 22];38(4):165–7. Available from: https://www.publish.csiro.au/ma/MA17059

4. Ramalingam AJ. History of Antibiotics and Evolution of Resistance. Res J Pharm Technol [Internet]. 2015 Dec 28 [cited 2024 Nov 22];8(12):1719–24. Available from: https://rjptonline.org/AbstractView.aspx?PID=2015-8-12-23

5. Cosgrove SE. The Relationship between Antimicrobial Resistance and Patient Outcomes: Mortality, Length of Hospital Stay, and Health Care Costs. Clinical Infectious Diseases [Internet]. 2006 Jan 15 [cited 2024 Nov 22];42(Supplement_2):S82–9. Available from: https://dx.doi.org/10.1086/499406

6. Tenover FC. Mechanisms of Antimicrobial Resistance in Bacteria. Am J Med. 2006 Jun 1;119(6):S3–10. 

7. Premanandh J, Samara BS, Mazen AN. Race Against Antimicrobial Resistance Requires Coordinated Action – An Overview. Front Microbiol. 2016 Feb 2;6:168431. 

8. Acar JF, Moulin G. Antimicrobial resistance: a complex issue. OIE Revue Scientifique et Technique. 2012;31(1)(1):23–31. 

9. Irwin KK, Renzette N, Kowalik TF, Jensen JD. Antiviral drug resistance as an adaptive process. Virus Evol [Internet]. 2016 Jan 1 [cited 2024 Nov 22];2(1). Available from: https://dx.doi.org/10.1093/ve/vew014

10. Cannon RD, Lamping E, Holmes AR, Niimi K, Baret P V., Keniya M V., et al. Efflux-mediated antifungal drug resistance. Clin Microbiol Rev [Internet]. 2009 Apr [cited 2024 Nov 22];22(2):291–321. Available from: https://journals.asm.org/doi/10.1128/cmr.00051-08

11. Wang J, Xu C, Lun ZR, Meshnick SR. Unpacking ‘Artemisinin Resistance.’ Trends Pharmacol Sci [Internet]. 2017 Jun 1 [cited 2024 Nov 22];38(6):506–11. Available from: http://www.cell.com/article/S0165614717300640/fulltext

12. Martínez-Trejo A, Ruiz-Ruiz JM, Gonzalez-Avila LU, Saldaña-Padilla A, Hernández-Cortez C, Loyola-Cruz MA, et al. Evasion of Antimicrobial Activity in Acinetobacter baumannii by Target Site Modifications: An Effective Resistance Mechanism. International Journal of Molecular Sciences 2022, Vol 23, Page 6582 [Internet]. 2022 Jun 13 [cited 2024 Nov 22];23(12):6582. Available from: https://www.mdpi.com/1422-0067/23/12/6582/htm

13. Uruén C, Chopo-Escuin G, Tommassen J, Mainar-Jaime RC, Arenas J. Biofilms as Promoters of Bacterial Antibiotic Resistance and Tolerance. Antibiotics 2021, Vol 10, Page 3 [Internet]. 2020 Dec 23 [cited 2024 Nov 22];10(1):3. Available from: https://www.mdpi.com/2079-6382/10/1/3/htm

14. Lou Z, Sun Y, Rao Z. Current progress in antiviral strategies. Trends Pharmacol Sci [Internet]. 2014 Feb 1 [cited 2024 Nov 22];35(2):86–102. Available from: http://www.cell.com/article/S0165614713002265/fulltext

15. Weber IT. Can We Design Drugs for HIV/AIDS that are Less Susceptible to Resistance? Future Med Chem [Internet]. 2015 Nov 1 [cited 2024 Nov 22];7(17):2301–4. Available from: https://www.tandfonline.com/doi/abs/10.4155/fmc.15.149

16. Engle K, Kumar G. Tackling multi-drug resistant fungi by efflux pump inhibitors. Biochem Pharmacol. 2024 Aug 1;226:116400. 

17. Hori Y, Shibuya K. Role of FKS Gene in the Susceptibility of Pathogenic Fungi to Echinocandins. Med Mycol J. 2018;59(2):E31–40. 

18. Tekwanl BL, Shukla OP, Ghatak S. Altered drug metabolism in parasitic diseases. Parasitology Today. 1988 Jan 1;4(1):4–10. 

19. Birnbaum J, Scharf S, Schmidt S, Jonscher E, Maria Hoeijmakers WA, Flemming S, et al. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science (1979) [Internet]. 2020 Jan 3 [cited 2024 Nov 22];367(6473):51–9. Available from: https://www.science.org/doi/10.1126/science.aax4735

20. Langendonk RF, Neill DR, Fothergill JL. The Building Blocks of Antimicrobial Resistance in Pseudomonas aeruginosa: Implications for Current Resistance-Breaking Therapies. Front Cell Infect Microbiol. 2021 Apr 16;11:665759. 

21. Hasan CM, Pottenger S, Green AE, Cox AA, White JS, Jones T, et al. Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance. JCI Insight. 2022 Nov 22;7(22).