Document Type : Review Article


1 Department of Pharmacology, Toxicology and Therapeutics, College of Medicine, University of Lagos, 101014, Nigeria

2 Department of Microbiology, Faculty of Biological Sciences, Mountain Top University, 110106, Nigeria

3 Department of Internal Medicine, National Hospital Abuja, Abuja, 900103, Nigeria

4 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Portharcourt, 500272, Nigeria

5 Department of Anatomy, Faculty of Basic Medical Science, Ladoke Akintola University Ogbomoso, 210274, Nigeria

6 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, 330105, Nigeria

7 Department of Biomedical Engineering, School of Engineering, University of Strathclyde, G1 1XQ, UK

8 Department of Microbiology, Faculty of Sciences, Adekunle Ajasin University, 342111, Nigeria

9 Department of Microbiology, Faculty of Life Sciences, University of Ilorin, 1515, Nigeria

10 Department of Medicine, University of Development Studies, NT-0272-1946, Ghana

11 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Jos, 930105, Nigeria

12 Department of Public Health, Faculty of Health Science, Imo State University, 460281, Nigeria

13 Department of Microbiology, School of Biological Sciences, Lagos State Polytechnic, 104233, Nigeria

14 Department of Pharmacy, Niger Delta University, Amassoma, 560103, Nigeria


Antibiotic resistance is becoming more prevalent, which presents as an urgent risk to world-wide well-being, necessitating an urgent exploration of its mechanisms, implications, and potential mitigation strategies. This review provides an overview of the growing antibiotic resistance phenomenon within the realm of gram-positive bacteria, with a specific focus on three major pathogens: Staphylococcus aureus, Enterococcus spp., and Streptococcus pneumoniae. These pathogens, once susceptible to conventional antibiotics, have displayed remarkable adaptability to develop resistance, rendering standard treatment regimens ineffective. This review outlines the objectives of understanding the mechanisms underlying the emergence of resistance, deciphering the clinical impact of resistance development, and highlighting the potential interventions to mitigate the crisis. This review also highlights a comprehensive exploration of the interaction between these pathogens and the selective pressure of antibiotics, horizontal gene transfer, and genetic mutations are central themes elucidated in this study. The clinical implications of these emerging resistance mechanisms, including treatment failure, increased morbidity, and mortality, emphasize the urgency of addressing this escalating concern.
Furthermore, this review underscores the importance of alternative strategies, such as combination therapies, synergistic approaches, and the revival of older antibiotics, in combating gram-positive bacterial resistance. The study aims to provide insights into the novel strategies that hold promise for the treatment of gram-positive bacterial infections that are resistant to antibiotics.
The review aims to contribute to the global efforts in curbing the antibiotic resistance crisis.

Graphical Abstract

Emerging Antibiotic Resistance in Gram-Positive Bacteria, with Focus on Staphylococcus Aureus, Enterococcus Spp., and Streptococcus Pneumoniae


Main Subjects


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  1. WHO, Health World Organization, Fact Sheet. 2020. [Cited on 2023 August 26] [Publisher]
  2. Kakoullis L, Papachristodoulou E, Chra P, Panos G. Mechanisms of antibiotic resistance in important gram-positive and gram-negative pathogens and novel antibiotic solutions. The Journal of Antibiotics, 2021 Apr 10;10(4):415. [Crossref], [Google Scholar], [Publisher]
  3. Algammal AM, Hetta HF, Elkelish A, Alkhalifah DHH, Hozzein WN, Batiha GE, El Nahhas N, Mabrok MA, Methicillin-resistant staphylococcus aureus (mrsa): one health perspective approach to the bacterium epidemiology, virulence factors, antibiotic-resistance, and zoonotic impact. Infection and Drug Resistance, 2020;13:3255-65 [Crossref], [Google Scholar], [Publisher]
  4. Lee AS, De Lencastre H, Garau J, Kluytmans J, Malhotra-Kumar S, Peschel A, Harbarth S, Methicillin-resistant Staphylococcus aureus. Nature Reviews Disease Primers, 2018(4):1-23. [Crossref], [Google Scholar], [Publisher]
  5. Michaelis C, Grohmann E. Horizontal gene transfer of antibiotic resistance genes in biofilms. The Journal of Antibiotics, 2023 Feb 4;12(2):328. [Crossref], [Google Scholar], [Publisher]
  6. Ayobami O, Willrich N, Reuss A, Eckmanns T, Markwart R. The ongoing challenge of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Europe: an epidemiological analysis of bloodstream infections. Emerging Microbes & Infections, 2020 Jan 1;9(1):1180-93. [Crossref], [Google Scholar], [Publisher]
  7. Pitcher NJ, Feder A, Bolden N, Zirbes CF, Pamatmat AJ, Boyken LD, Hill JJ, Thurman A, Reeb V, Porterfield HS, Moustafa AM. Parallel evolution of linezolid resistant staphylococcus aureus in patients with cystic fibrosis. BioRxiv. 2023. [Crossref], [Google Scholar], [Publisher]
  8. Cillóniz C, Garcia-Vidal C, Ceccato A, Torres A. Antimicrobial resistance among Streptococcus pneumoniae. In Antimicrobial Resistance in the 21st Century. I. W. Fong, David Shlaes Karl Drlica; editors Springer International Publishing AG, part of Springer Nature 2018 2nd ed:13 38. [Crossref], [Google Scholar], [Publisher]
  9. McCarthy N, Deaths from drug-resistant infections set to skyrocket. 2015. [Google Scholar]
  10. Jubeh B, Breijyeh Z, Karaman R. Resistance of gram-positive bacteria to current antibacterial agents and overcoming approaches. Molecules. 2020 Jun 23;25(12):2888. [Crossref], [Google Scholar], [Publisher]
  11. Miragaia M. Factors contributing to the evolution of mecA-mediated β-lactam resistance in staphylococci: update and new insights from whole genome sequencing (WGS). Frontiers in Microbiology. 2018 Nov 13;9:2723. [Crossref], [Google Scholar], [Publisher]
  12. Turner NA, Sharma-Kuinkel BK, Maskarinec SA, Eichenberger EM, Shah PP, Carugati M, Holland TL, Fowler Jr VG. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nature Reviews Microbiology. 2019 Apr;17(4):203-18. [Crossref], [Google Scholar], [Publisher]
  13. Levitus, Matthew, Ayesan Rewane, and Thomas B. Perera. "Vancomycin-resistant enterococci." StatPearls [Internet]. StatPearls Publishing, 2022.
  14. Partridge SR, Kwong SM, Firth N, Jensen SO. Mobile genetic elements associated with antimicrobial resistance. Clinical microbiology Reviews. 2018 Oct;31(4):10-128. [Crossref], [Google Scholar], [Publisher]
  15. da Silva GC, Gonçalves OS, Rosa JN, França KC, Bossé JT, Santana MF, Langford PR, Bazzolli DM. Mobile genetic elements drive antimicrobial resistance gene spread in pasteurellaceae species. Frontiers in Microbiology. 2022 Jan 6;12:773284. [Crossref], [Google Scholar], [Publisher]
  16. Liu Y, Tong Z, Shi J, Li R, Upton M, Wang Z. Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria. Theranostics. 2021;11(10):4910. [Crossref], [Google Scholar], [Publisher]
  17. Di Ruscio F, Guzzetta G, Bjørnholt JV, Leegaard TM, Moen AE, Merler S, Freiesleben de Blasio B. Quantifying the transmission dynamics of MRSA in the community and healthcare settings in a low-prevalence country. Proceedings of the National Academy of Sciences. 2019 Jul 16;116(29):14599-605. [Crossref], [Google Scholar], [Publisher]
  18. Alsolami A, ALGhasab NS, Alharbi MS, Bashir AI, Saleem M, Syed Khaja AS, Aldakheel DF, Rakha E, Alshammari JA, Taha TE, Melibari Z. Community-acquired methicillin-resistant staphylococcus aureus in hospitals: age-specificity and potential zoonotic–zooanthroponotic transmission dynamics. Diagnostics. 2023 Jun 16;13(12):2089. [Crossref], [Google Scholar], [Publisher]
  19. Pajohesh R, Tajbakhsh E, Momtaz H, Rahimi E. Relationship between Biofilm Formation and Antibiotic Resistance and Adherence Genes in Staphylococcus aureus Strains Isolated from Raw Cow Milk in Shahrekord, Iran. International Journal of Microbiology. 2022 Oct 25;2022. [Crossref], [Google Scholar], [Publisher]
  20. Malachowa N, DeLeo FR. Mobile genetic elements of Staphylococcus aureus. Cellular and Molecular Life Sciences. 2010 Sep;67:3057-71. [Crossref], [Google Scholar], [Publisher]
  21. Dashtbani-Roozbehani A, Brown MH. Efflux pump mediated antimicrobial resistance by staphylococci in health-related environments: challenges and the quest for inhibition. Antibiotics. 2021 Dec 7;10(12):1502. [Crossref], [Google Scholar], [Publisher]
  22. Liu C, Hong Q, Chang RY, Kwok PC, Chan HK. Phage–Antibiotic therapy as a promising strategy to combat multidrug-resistant infections and to enhance antimicrobial efficiency. Antibiotics. 2022 Apr 25;11(5):570. [Crossref], [Google Scholar], [Publisher]
  23. Ling H, Lou X, Luo Q, He Z, Sun M, Sun J. Recent advances in bacteriophage-based therapeutics: Insight into the post-antibiotic era. Acta Pharmaceutica Sinica B. 2022 Dec 1;12(12):4348-64. [Crossref], [Google Scholar], [Publisher]
  24. Ramos S, Silva V, Dapkevicius MD, Igrejas G, Poeta P. Enterococci, from harmless bacteria to a pathogen. Microorganisms. 2020 Jul 25;8(8):1118. [Crossref], [Google Scholar], [Publisher]
  25. Wada Y, Harun AB, Yean CY, Zaidah AR. Vancomycin-resistant enterococci (VRE) in Nigeria: the first systematic review and meta-analysis. Antibiotics. 2020 Sep 1;9(9):565. [Crossref], [Google Scholar], [Publisher]
  26. Young S, Nayak B, Sun S, Badgley BD, Rohr JR, Harwood VJ. Vancomycin-resistant enterococci and bacterial community structure following a sewage spill into an aquatic environment. Applied and Environmental Microbiology. 2016 Sep 15;82(18):5653-60. [Crossref], [Google Scholar], [Publisher]
  27. Zarzecka U, Zakrzewski AJ, Chajęcka-Wierzchowska W, Zadernowska A. Linezolid-Resistant Enterococcus spp. Isolates from Foods of Animal Origin—The Genetic Basis of Acquired Resistance. Foods. 2022 Mar 28;11(7):975. [Crossref], [Google Scholar], [Publisher]
  28. Leão C, Clemente L, Cara d’Anjo M, Albuquerque T, Amaro A. Emergence of Cfr-Mediated Linezolid Resistance among Livestock-Associated Methicillin-Resistant Staphylococcus aureus (LA-MRSA) from Healthy Pigs in Portugal. Antibiotics. 2022 Oct 19;11(10):1439. [Crossref], [Google Scholar], [Publisher]
  29. Dutt Y, Dhiman R, Singh T, Vibhuti A, Gupta A, Pandey RP, Raj VS, Chang CM, Priyadarshini A. The association between biofilm formation and antimicrobial resistance with possible ingenious bio-remedial approaches. Antibiotics. 2022 Jul 11;11(7):930. [Crossref], [Google Scholar], [Publisher]
  30. Dai W, Zhang Y, Zhang J, Xue C, Yan J, Li X, Zheng X, Dong R, Bai J, Su Y, Xie P. Analysis of antibiotic-induced drug resistance of Salmonella enteritidis and its biofilm formation mechanism. Bioengineered. 2021 Dec 20;12(2):10254-63. [Crossref], [Google Scholar], [Publisher]
  31. Konwar AN, Hazarika SN, Bharadwaj P, Thakur D. Emerging Non-Traditional Approaches to Combat Antibiotic Resistance. Current Microbiology. 2022 Nov;79(11):330. [Crossref], [Google Scholar], [Publisher]
  32. Weiser JN, Ferreira DM, Paton JC. Streptococcus pneumoniae: transmission, colonization and invasion. Nature Reviews Microbiology. 2018 Jun;16(6):355-67. [Crossref], [Google Scholar], [Publisher]
  33. Ung L, Bispo PJ, Bryan NC, Andre C, Chodosh J, Gilmore MS. The best of all worlds: Streptococcus pneumoniae conjunctivitis through the lens of community ecology and microbial biogeography. Microorganisms. 2019 Dec 25;8(1):46. [Crossref], [Google Scholar], [Publisher]
  34. Duke JA, Avci FY. Emerging vaccine strategies against the incessant pneumococcal disease. NPJ Vaccines. 2023 Aug 17;8(1):122. [Crossref], [Google Scholar], [Publisher]
  35. Baran A, Kwiatkowska A, Potocki L. Antibiotics and Bacterial Resistance—A Short Story of an Endless Arms Race. International Journal of Molecular Sciences. 2023 Mar 17;24(6):5777. [Crossref], [Google Scholar], [Publisher]
  36. Saha M, Sarkar A. Review on multiple facets of drug resistance: a rising challenge in the 21st century. Journal of Xenobiotics. 2021 Dec 13;11(4):197-214. [Crossref], [Google Scholar], [Publisher]
  37. Rodgers GL, Whitney CG, Klugman KP. Triumph of pneumococcal conjugate vaccines: overcoming a common foe. The Journal of Infectious Diseases. 2021 Oct 1;224(Supplement_4):S352-9. [Crossref], [Google Scholar], [Publisher]
  38. Kim SH, Chung DR, Song JH, Baek JY, Thamlikitkul V, Wang H, Carlos C, Ahmad N, Arushothy R, Tan SH, Lye D. Changes in serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates from adult patients in Asia: emergence of drug-resistant non-vaccine serotypes. Vaccine. 2020 Aug 27;38(38):6065-73. [Crossref], [Google Scholar], [Publisher]
  39. Cherazard R, Epstein M, Doan TL, Salim T, Bharti S, Smith MA. Antimicrobial resistant Streptococcus pneumoniae: prevalence, mechanisms, and clinical implications. American journal of Therapeutics. 2017 May 1;24(3):e361-9. [Crossref], [Google Scholar], [Publisher]
  40. Velazquez-Meza ME, Galarde-López M, Carrillo-Quiróz B, Alpuche-Aranda CM. Antimicrobial resistance: one health approach. Veterinary World. 2022 Mar;15(3):743. [Crossref], [Google Scholar], [Publisher]