Using Next-Generation Antibiotics to Combat Antimicrobial Resistance

The Antibiotic Resistance Crisis 

Antibiotics have been instrumental in treating bacterial infections, saving countless lives since their discovery. However, their misuse and overuse in humans, animals, and plants are the main drivers in developing drug-resistant pathogens. 

AMR takes a substantial toll on the economy and global health, with the CDC estimating an annual cost of $55 billion in the United States alone.  

In late 2023, the WHO declared the spread of AMR as one of the top 10 threats to global health and development, demonstrating that multidrug-resistant bacteria negatively impact various aspects of society, affecting countries worldwide regardless of income level. Still, poverty and inequality exacerbate the drivers and consequences of this issue, with low- and middle-income countries being hit the hardest. 

During COVID-19, the spread of AMR had been intensified by infection control lapses, with significantly higher rates of hospital-acquired infections and deaths from multidrug-resistant bacteria in US hospitals. It is estimated that infections from multidrug-resistant bacteria could cause more than 10 million deaths per year worldwide by 2050. 

To address this compounding crisis, scientists and researchers are directing their efforts toward developing next-generation antibiotics. 

Challenges in Antibiotic Development 

Developing new antibiotics is an intricate process that involves tackling several challenges. One major obstacle is the high cost of research and development, coupled with the relatively low financial return on investment for pharmaceutical companies. For instance, the median price of developing new antibiotics surpasses $1 billion, with estimated post-approval expenses for regulatory compliance, manufacturing, and distribution totaling $350 million over a decade. 

The lengthy and expensive clinical trial process and regulatory hurdles further contribute to the challenges. Additionally, discovering new antibiotics is becoming increasingly difficult due to the limited number of novel compounds. This has led researchers to explore alternative strategies, including repurposing existing drugs and developing innovative approaches. 

Next-Generation Antibiotic Approaches 

Next-generation antibiotic approaches include Gram-negative bacteria targeting, combination therapies, immunotherapy, bacteriophage therapy, and CRISPR–Cas systems. 

Targeting Gram-Negative Bacteria 

Gram-negative bacteria, such as Escherichia coli and Pseudomonas aeruginosa, have an outer membrane as a protective barrier, making them inherently antibiotic-resistant. Scientists are working on novel strategies to overcome this challenge, including developing drugs that penetrate the outer membrane or disrupt the bacterial cell wall. Several innovative approaches are being explored, such as using efflux pump inhibitors to prevent the bacteria from pumping out antibiotics and developing antimicrobial peptides to restrict bacterial activity. 

Combination Therapies 

Combining multiple antibiotics can enhance their effectiveness and reduce the likelihood of resistance. This approach is beneficial for treating multidrug-resistant infections. By targeting different aspects of bacterial metabolism or cell structure, combination therapies can increase treatment efficacy and reduce the emergence of resistance. Some examples include combining a beta-lactam antibiotic with a beta-lactamase inhibitor to overcome resistance mechanisms or using a combination of antibiotics that target different cellular processes within the bacteria. 

Immunotherapy 

Immunotherapy harnesses the power of the immune system to fight bacterial infections. For example, monoclonal antibodies can specifically target and neutralize bacterial toxins or virulence factors. This approach offers a potential alternative to traditional antibiotics and can be used alongside existing treatments. Immunotherapies can also boost the immune response, enhancing the body's ability to clear bacterial infections. Research in this area is focused on identifying specific targets on bacterial surfaces or toxins that can be targeted by antibodies or developing vaccines to prevent bacterial infections. 

Bacteriophage Therapy 

Bacteriophages are viruses that selectively infect and kill bacteria. They offer a promising avenue for treating antibiotic-resistant infections. Bacteriophage therapy has succeeded in clinical trials, particularly for infections caused by multidrug-resistant bacteria like Staphylococcus aureus and Klebsiella pneumoniae. Phages are isolated from the environment or engineered in the laboratory to target specific bacterial strains. They can be highly specific to the target bacteria, leaving the rest of the body's microbiome intact. However, challenges still need to be addressed regarding standardization, regulatory approval, and the development of phage cocktails that can effectively target a wide range of bacterial strains. 

CRISPR–Cas Systems 

CRISPR–Cas systems, known for their gene-editing capabilities, can also be repurposed to target and destroy antibiotic-resistant bacteria. Researchers can selectively eliminate resistant strains by programming CRISPR–Cas systems to cleave specific bacterial DNA sequences while leaving the non-resistant strains unharmed. This approach holds great promise for combating antibiotic resistance, as it can target the genetic mechanisms responsible for resistance directly. However, further research is needed to optimize the delivery and specificity of CRISPR–Cas systems for clinical applications. 

Emerging Technologies and Innovations 

Several emerging technologies are revolutionizing antibiotic development, including artificial intelligence (AI), nanotechnology, synthetic biology, and microbiome-based therapies. 

AI 

AI-powered algorithms can analyze vast amounts of data to identify potential drug candidates, predict antibiotic resistance, and optimize drug design. This technology accelerates discovery by identifying patterns and relationships that humans may overlook. AI can also be used to model the spread of antibiotic resistance and predict the effectiveness of different treatment strategies, aiding in developing targeted and personalized antibiotic therapies. 

Nanotechnology 

Nanotechnology can be used to develop novel antimicrobial coatings for medical devices, preventing the formation of biofilms and reducing the risk of device-related infections.  

Nanoparticles can also be engineered to deliver antibiotics selectively to the site of infection. This targeted drug delivery approach reduces systemic side effects and enhances treatment efficacy. However, clinical use currently needs to be improved to address the long-term effects of nanoparticles on patients and systemic safety. 

Synthetic Biology 

Synthetic biology techniques enable the creation of novel antibiotics by redesigning existing microbial pathways or engineering entirely synthetic organisms. This approach provides a powerful tool for producing new antibiotics and overcoming resistance. By introducing genetic modifications, researchers can enhance the potency and spectrum of existing antibiotics or develop entirely new compounds with unique mechanisms of action. 

Microbiome-Based Therapies 

The human microbiome, which consists of trillions of microorganisms that inhabit our bodies, plays a crucial role in health and disease. Researchers are exploring the use of microbiome-based therapies to combat antibiotic-resistant infections. These therapies use beneficial bacteria or their byproducts to restore a healthy microbial balance and prevent the overgrowth of antibiotic-resistant strains. For example, fecal microbiota transplantation (FMT) has shown promising results in treating recurrent Clostridium difficile infections. 

By investing in research, policy support, and global cooperation, addressing the challenges of AMR will become more manageable. Industry professionals are urged to advocate responsible antibiotic usage, enhance surveillance systems for resistance monitoring, and foster collaboration among academia, industry, and regulatory entities to expedite next-generation antibiotic development and availability. Embracing these advancements and adopting a comprehensive, multidisciplinary approach can pave the way for a post-antibiotic era with readily available effective treatments for resistant infections, thereby mitigating the threat of antimicrobial resistance.