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Combating antibacterial resistance: Innovations in drug design

The global impact of antibacterial resistance
Drug development strategies to overcome antibacterial resistance
Future research outlook
References

Antibiotic resistance occurs when antibiotics cannot treat bacterial infections. This occurrence is considered one of the greatest global health threats and is due to the misuse or overuse of antibiotics in humans and animals.1

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The global impact of antibacterial resistance

Bacterial infections are common and can affect various organs and tissues in the human body.² Doctors typically prescribe antibiotics to treat these infections; However, many bacteria have developed resistance to these treatments, including those considered the “last line of defense,” such as vancomycin and polymyxin. The prevalence of multidrug-resistant (MDR) bacteria is well documented.

In 2015, the World Health Organization launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS) to monitor antibiotic resistance worldwide.³ GLASS data from 2022 showed a significant increase in antibiotic resistance, which increases the effectiveness of commonly used antibiotics against widespread bacterial infections.

Methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Escherichia coli (E. coli) have been reported in 76 countries. In 2020, one in five people were diagnosed with a urinary tract infection caused by E. coli and showed a decreased response to commonly prescribed antibiotics such as ampicillin, fluoroquinolones and co-trimoxazole. In addition, Klebsiella pneumoniae, an intestinal bacterium, showed increased antibiotic resistance.³

The Organization for Economic Co-operation and Development (OECD) predicts that resistance to last-resort antibiotics will double by 2035. These results highlight the urgent need for innovative strategies to combat antibacterial resistance and highlight the importance of expanding global surveillance efforts.

The importance of antimicrobial management in the fight against AMR

What causes antibiotic resistance? -Kevin Wu

Drug development strategies to overcome antibacterial resistance

Most currently available antibiotics are based on discoveries made before 2010. Given the increasing antibacterial resistance to many common antibiotics, there is an urgent need to develop new antibacterial agents that can act effectively against a wide range of bacterial strains. Below are some of the key innovative drug design strategies being investigated to combat bacterial resistance.

Antimicrobial peptides (AMPs)

A number of AMPs have been developed to combat bacterial resistance.⁴ For example, the antibiofilm peptide SAAP-148, derived from the parent peptide LL-37, has shown high efficacy against MDR pathogens.⁵ Proline-rich AMPs (PrAMPs), with multiple intracellular targets and low toxicity are promising candidates, particularly for the elimination of gram-negative pathogens. Commercially available antimicrobial peptides such as polymyxin and Bacillus short peptide are currently used for therapeutic purposes.

Adjuvants

Efflux pump inhibitors (EPIs) and enzymatic inhibitors are often used as adjuvants to improve antibiotic effectiveness.⁶ For example, β-lactamase inhibitors are combined with β-lactam antibiotics to prevent hydrolysis of the antibiotic's lactam ring, thereby improving its structural integrity and antibacterial activity to maintain effectiveness.

Efflux pumps contribute significantly to intrinsic and acquired bacterial resistance.⁷ Current research focuses on identifying and inhibiting EPIs to restore the effectiveness of existing antibiotics. For example, NorA, a chromosomally encoded multidrug efflux pump in MRSA, can be inhibited with synthetic antigen-binding fragments (Fabs).⁸

Nanomaterials

Metal-based nanomaterials, including zinc, silver and gold, are used to detect and treat bacterial infections. The antibacterial properties of these nanomaterials depend on their shape, size and composition. Silver nanoparticles are widely used in biosensing, drug delivery, and antimicrobial wound dressings. Current research results underline the effectiveness of gold nanoparticles against antibiotic-resistant bacteria.⁹

Cationic polymers

Cationic polymers such as chitosan, polyquaternary ammonium salts (PQAS), and polyethyleneimine (PEI) possess intrinsic antibacterial properties.¹⁰ These positively charged materials interact with negatively charged bacterial surfaces, damaging bacterial cell walls or membranes and causing bacterial cell death.

Phytochemicals

Plants produce secondary metabolites with antibacterial properties such as phenols, coumarin alkaloids and organosulfur compounds, which are found in seeds, roots, leaves, stems, flowers and fruits.¹¹ These compounds are promising candidates for combating antibacterial resistance.

Plant extracts and essential oils are currently being studied for their potential to alter antibiotic resistance in bacteria. Mechanistically, secondary metabolites inhibit efflux pumps, biofilm synthesis, bacterial cell wall synthesis, and bacterial physiology, thereby modulating antibiotic susceptibility. Studies show that alkaloids and phenolic compounds can inhibit the efflux pumps in Staphylococcus aureus, E. coli and MRSA.

RNA silencing

RNA silencing, a natural bacterial gene regulation mechanism, involves complementary cis and trans sequences that interact with regulatory regions on the mRNA (antisense sequences). Synthetic antisense sequences can be designed to inhibit translation of resistance-associated enzymes.¹²

CRISPR-Cas system

The CRISPR-Cas (clustered regularly interspersed short palindromic repeats-associated protein) system is an adaptive immune system in bacteria that protects against viruses, phages and foreign genetic material.¹³

As a genetic engineering tool, CRISPR-Cas can specifically target and alter bacterial genomes, potentially reducing or eliminating antibiotic resistance. This strategy shows promise in treating MDR infections.¹⁴

Phage therapy

Although phage therapy has been available for decades, its use declined with the advent of antibiotics. The recent rise in antibiotic resistance has reignited interest in phage therapy. For example, phage therapy was able to successfully treat a cystic fibrosis patient who was infected with a drug-resistant infection Mycobacteroides abscessus.¹⁵ Bacteriophages have also been shown to be effective in treating elderly patients with S. aureus prosthetic joint infections.¹⁶

Drug delivery systems

Drug delivery systems (DDS) increase the biodistribution and bioavailability of antibiotics. This strategy can effectively reduce antibiotic resistance and extend the lifespan of novel antibiotics. Scientists have adopted a “Trojan horse” strategy in the design and development of DDSs.

This strategy combines antibacterial agents with various carriers such as exosomes, liposomes, erythrocytes, self-assembled peptides and polymers. By targeting the unique microenvironment of the infected tissue or using external control, DDSs enable drug release at the specific site.16

Together against antimicrobial resistance: An interview with the World Health Organization

Future research outlook

The availability of different types of antibiotics led to the development of complex resistance mechanisms, in particular to the emergence of MDR bacteria. To counteract this situation, scientists are focusing on uncovering the bactericidal mechanism of antibiotics and the mechanism of bacterial resistance.

Advances in materials science, nanotechnology and gene editing tools have opened up a wide range of opportunities for this line of research. DDS technology has also shown enormous potential in overcoming bacterial resistance in the future.

References

  1. Mancuso G, et al. Bacterial antibiotic resistance: The most critical pathogens. pathogens. 2021;10(10):1310. doi: 10.3390/pathogens10101310.
  2. Doron S, Gorbach SL. Bacterial infections: overview. International Encyclopedia of Public Health. 2008:273–82. doi: 10.1016/B978-012373960-5.00596-7.
  3. Antimicrobial resistance. World Health Organization; 2023; Reviewed October 5, 2024.
  4. Xuan J, et al. Antimicrobial peptides to combat drug-resistant bacterial infections. Drug Resistance Updates. 2023; 68, 100954. doi.org/10.1016/j.drup.2023.100954
  5. Shi J et al. The antimicrobial peptide LI14 fights multi-resistant bacterial infections. Municipal Biol. 2022;5, 926. doi.org/10.1038/s42003-022-03899-4
  6. El-Khoury C, et al. The role of adjuvants in overcoming antibacterial resistance due to enzymatic drug modification. RSC Med Chem. 2022;13(11):1276-1299. doi: 10.1039/d2md00263a.
  7. Gaurav A, et al. Role of bacterial efflux pumps in antibiotic resistance, virulence and strategies for the discovery of new efflux pump inhibitors. Microbiology (reading). 2023;169(5):001333. doi: 10.1099/mic.0.001333.
  8. Brawley DN, et al. Structural basis for the inhibition of the drug efflux pump NorA from Staphylococcus aureus. Nat Chem Biol. 2022;18(7):706-712. doi: 10.1038/s41589-022-00994-9.
  9. Rizvi SMD et al. Antibiotic-loaded gold nanoparticles: A nano-arsenal against ESBL producer-resistant pathogens. pharmacy. 2023;15(2):430. doi: 10.3390/pharmaceutics15020430.
  10. Carmona-Ribeiro AM, de Melo Carrasco LD. Cationic antimicrobial polymers and their compositions. Int J Mol Sci. 2013;14(5):9906-46. doi: 10.3390/ijms14059906.
  11. Ashraf MV, et al. Phytochemicals as Antimicrobials: Exploring Himalayan Medicinal Plants as a Source of Alternative Medicine to Combat Antimicrobial Resistance. drug. 2023; 16(6):881. doi.org/10.3390/ph16060881
  12. Jani S, et al. Suppression of antibiotic resistance with antisense oligonucleotides. Biomedicine. 2021;9(4):416. doi: 10.3390/biomedicines9040416.
  13. Xu Y, Li Z. CRISPR-Cas systems: Overview, innovations and applications in human disease research and gene therapy. Comput Struct Biotechnol J. 2020;18:2401-2415. doi: 10.1016/j.csbj.2020.08.031.
  14. Tao S, et al. The application of the CRISPR-Cas system in antibiotic resistance. Infect drug resistance. 2022;15:4155-4168. doi: 10.2147/IDR.S370869.
  15. Recchia D, et al. Mycobacterium abscessus Infections in Cystic Fibrosis Patients: A Review of Therapeutic Options. Int J Mol Sci. 2023;24(5):4635. doi: 10.3390/ijms24054635.
  16. Yao J, et al. Recent Advances in Strategies to Combat Bacterial Drug Resistance: Antimicrobial Materials and Drug Delivery Systems. pharmacy. 2023;15(4):1188. doi: 10.3390/pharmaceutics15041188.

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