Innovative Drug-Design Strategies to Overcome Antibacterial Resistance

Antibacterial resistance occurs when antibiotics fail to treat bacterial infections. This incidence is considered one of the top global health threats, stemming from the misuse or overuse of antibiotics in humans and animals.¹

The global impact of antibacterial resistance

Bacterial infections are common and can impact various organs and tissues in the human body.² Clinicians 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 multi-drug-resistant (MDR) bacteria is well-documented.

In 2015, the World Health Organization initiated the Global Antimicrobial Resistance and Use Surveillance System (GLASS) to monitor antimicrobial resistance globally.³ The 2022 GLASS data showed a significant rise in antibiotic resistance, reducing 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 individuals was diagnosed with urinary tract infections caused by E. coli, which showed reduced responsiveness to commonly prescribed antibiotics, including ampicillin, fluoroquinolones, and co-trimoxazole. Additionally, Klebsiella pneumoniae, an intestinal bacterium, exhibited increased antibiotic resistance.³

The Organization for Economic Cooperation and Development (OECD) projects a twofold increase in resistance to last-resort antibiotics by 2035. These findings emphasize the urgent need for innovative strategies to combat antibacterial resistance and underscore the importance of expanding global surveillance efforts.

Drug-design strategies to overcome antibacterial resistance

Most currently available antibiotics are derived from 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 effectively target a broad range of bacterial strains. Below are some of the key innovative drug-design strategies being explored to address bacterial resistance.

Antimicrobial Peptides (AMPs)

A range of AMPs have been designed to combat bacterial resistance.⁴ For instance, 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, especially for eliminating Gram-negative pathogens. Commercially available peptide antimicrobials, such as polymyxin and short bacillus peptide, are currently used for therapeutic purposes.

Adjuvants

Efflux pump inhibitors (EPIs) and enzymatic inhibitors are commonly used as adjuvants to enhance antibiotic efficacy.⁶ For example, β-lactamase inhibitors are combined with β-lactam antibiotics to prevent the hydrolysis of the antibiotic's lactam ring, preserving its structural integrity and antibacterial effectiveness.

Efflux pumps contribute significantly to both intrinsic and acquired bacterial resistance.⁷ Current research focuses on identifying and inhibiting EPIs to restore the potency of existing antibiotics. For instance, 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 utilized for bacterial infection detection and treatment. 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. Recent research highlights the effectiveness of gold nanoparticles against antibiotic-resistant bacteria.⁹

Cationic polymers, such as chitosan, polyquaternary ammonium salts (PQASs), 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 leading to bacterial cell death.

Phytochemicals

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

Plant extracts and essential oils are under study for their potential to modify bacterial antibiotic resistance. Mechanistically, secondary metabolites inhibit efflux pumps, biofilm synthesis, bacterial cell wall synthesis, and bacterial physiology, 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 mRNA (antisense sequences). Synthetic antisense sequences can be designed to inhibit the translation of resistance-associated enzymes.¹²

CRISPR-Cas system

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

As a genetic engineering tool, CRISPR-Cas can selectively target and modify 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 successfully treated a cystic fibrosis patient infected with drug-resistant Mycobacteroides abscessus.¹⁵ Bacteriophages have also shown efficacy in treating elderly patients with S. aureus prosthetic joint infections.¹⁶

Drug delivery systems

Drug delivery systems (DDSs) increase antibiotic biodistribution and bioavailability. This strategy can effectively reduce antibiotic resistance and prolong novel antibiotics' lifespan. Scientists adopted a "Trojan horse" strategy in designing and developing DDSs.

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

Future research outlook

The availability of various antibiotic types resulted in the development of complex mechanisms of resistance, particularly the emergence of MDR bacteria. To combat the situation, scientists are focused on uncovering the bactericidal mechanism of antibiotics and the mechanism of bacterial resistance.

The advancements in material science, nanotechnology, and gene editing tools have presented multiple opportunities for this strand of research. DDS technology has also exhibited immense potential in helping overcome bacterial resistance in the future.

References

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