Battling an Invisible Enemy

Antibiotic resistance is becoming a critical global health issue, threatening the effectiveness of treatments for infections. As bacteria evolve to resist existing drugs, new strategies and collaborative efforts are essential to combat this growing threat. From advanced research techniques to innovative therapies, the world is mobilising to protect public health against superbugs.
By Deepika Pandey and Mukesh Nandave

Antibiotic resistance (AR) is one of the most pressing issues we face today. It threatens our ability to treat infections, impacts public health, disrupts food security, and hinders global development. This problem started not long after the first antibiotic was discovered. When bacteria become resistant to antibiotics, it becomes harder to treat infections in both people and animals. This leads to higher medical costs, longer hospital stays, and more deaths.
The World Health Organization (WHO) estimates that AR could cause about 10 million deaths each year. Even though we know how serious AR is, we still struggle to develop new antibiotics, and the ones we desperately need are not being created fast enough.

Why AR is Such a Big Problem
The more we use antibiotics, the more we push bacteria to become resistant. Our modern lifestyle, with dense populations and rapid travel, makes it easier for resistant bacteria to spread. Bacteria have clever ways to survive antibiotics. They can change their genetic makeup through mutations or by picking up resistance genes from other bacteria.

Here’s how bacteria become resistant:

1.Reduced Affinity: Bacteria can alter themselves so that antibiotics can’t easily bind to them.
2.Antibiotic Inactivation: Bacteria produce enzymes that break down antibiotics, rendering them ineffective.
3.Membrane Changes: Bacteria can change their cell membranes to prevent antibiotics from entering.
4.Efflux Pumps: Bacteria can develop pumps that actively expel antibiotics from their cells, preventing the drugs from working.
These mechanisms make it increasingly difficult to treat infections, emphasising the need for new antibiotics and better management of existing ones to combat AR effectively.

Antibiotic Resistance: An Emerging Challenge
Developing new technologies has helped us find new ways to fight antibiotic resistance. For example, we can now study biological systems, such as metabolic pathways and immune responses, to develop novel strategies against resistant bacteria.

How Bacteria Respond to Stress and Develop Resistance
Bacteria face many stressful conditions like acidity, heat, cold, hunger, and oxidative stress. These stresses trigger bacterial responses that help them survive and adapt. Unfortunately, these responses can also make bacteria resistant to antibiotics. For instance, Gram-negative bacteria become resistant by reducing membrane permeability, altering target sites, producing enzymes that destroy antibiotics, increasing efflux pump activity, and changing metabolic pathways. These stress responses make it harder for antibiotics to work effectively.

The SOS Response: A Key Player in Resistance
The SOS response is a well-known bacterial reaction to DNA damage caused by stressors such as high pressure, acid, oxidants, and antibiotics. This response involves reactive oxygen species (ROS) that damage DNA. Two key genes, LexA (a repressor) and RecA (an inducer), regulate the SOS response. When DNA is damaged, the RecA-ATP complex accumulates and triggers the self-cleavage of LexA, leading to the expression of SOS genes. This process helps bacteria repair their DNA but also contributes to antibiotic resistance by promoting biofilm formation and genetic changes.

Heat and Cold Stress: Their Role in Resistance
Bacteria respond to sudden temperature changes through heat shock response (HSR) and cold shock response (CSR). During HSR, bacteria produce heat shock proteins (HSPs) that help refold damaged proteins and degrade faulty ones. HSPs like ClpLA and ClpXP are associated with antibiotic resistance. HSR also increases genetic recombination and horizontal gene transfer, contributing to multidrug resistance in Gram-negative bacteria.
During CSR, cold shock proteins (CSPs) help bacteria initiate protein synthesis under cold conditions. CSPs like CspD promote biofilm formation and the development of persister cells, which are highly resistant to antibiotics. Additionally, low temperatures can alter the expression of porins and membrane fusion proteins, further enhancing resistance in bacteria like Moraxella catarrhalis.

Our Microbiome: Maintaining Health Balance
Our microbiome, the community of microbes living in and on our bodies, plays a crucial role in our overall health. It forms an interconnected network involving bacteria, bacteriophages (viruses that infect bacteria), and human cells. Disrupting this balance, such as through exposure to external phages, can affect the stability of our microbiome, impacting our immune and metabolic health.
By understanding these processes and developing new strategies, we can better combat antibiotic resistance and protect public health.
Microbial dysbiosis, or immune dysregulation, may have significant consequences for our immunologic and metabolic health. Tri-Kingdom interaction in our microbiome accountable for maintaining immune system and metabolic health.
Antibiotic resistance is becoming a bigger problem because of the overuse and misuse of antibiotics, as well as poor infection control and prevention. Everyone has a role to play in addressing this issue, including individuals, medical professionals, veterinarians, governments, and non-governmental organisations.

How Individuals Can Help Prevent Antibiotic Resistance
• Use Antibiotics Responsibly: Only take antibiotics when prescribed by a certified health professional.
• Practice Good Hygiene: Regular hand washing and other hygiene practices can help prevent infections and reduce the need for antibiotics.

How Policymakers Can Encourage Responsible Antibiotic Use
• Develop National Action Plans: Create and strengthen policies to prevent the overuse of antibiotics and control infections.
• Improve Surveillance and Awareness: Monitor antibiotic-resistant infections and educate the public about the dangers of antibiotic resistance.

The Role of Health Professionals
• Prevent Hospital-Acquired Infections: Develop comprehensive plans and educate medical staff and patients about infection prevention and control (IPC) practices.
• Raise Awareness: Spread knowledge about antibiotic resistance and the importance of preventing infections.

How the Industry Can Innovate to Prevent Antibiotic Resistance
• Invest in Research: Focus on developing new medicines, vaccines, diagnostics, and other technologies to prevent infections.
• Prioritise Antibiotic Resistance: Allocate funds and resources to address this critical issue.

Ensuring Responsible Use of Antibiotics in Agriculture
• Vaccinate Animals: Use vaccines to prevent diseases and give antibiotics only under veterinary supervision.
• Avoid Using Antibiotics for Growth Promotion: Do not use antibiotics to promote growth or prevent diseases in healthy animals.
• Practice Good Food Production: Follow best practices in producing and processing foods from animals and plants.

The Global Action Plan by WHO Against Antibiotic Resistance
The World Health Organization (WHO) has made fighting antibiotic resistance a top priority. In May 2015, the World Health Assembly approved a global action plan with five key goals:
1. Increase Knowledge and Awareness: Educate the public and professionals about antimicrobial resistance.
2. Improve Research and Surveillance: Enhance the monitoring and research of antibiotic resistance.
3. Reduce Infection Rates: Implement measures to lower the likelihood of infections.
4. Optimise Antibiotic Use: Promote the best possible use of antibiotics.
5. Ensure Sustainable Investment: Secure long-term funding and resources to combat antibiotic resistance.
By taking these actions, we can work together to slow the spread of antibiotic resistance and protect public health.

Call for Action in Research and Development
The rise of drug-resistant bacteria highlights the urgent need to understand how antimicrobial resistance (AMR) works, such as identifying specific genes responsible for resistance. The WHO has emphasised the theme, “Combat drug resistance: no action today means no cure tomorrow,” which has spurred increased research activities. Promising strategies have been developed to restore effective treatments against infections caused by resistant bacteria.

Rapid Identification and Quantification of Resistance
To tackle AMR effectively, it’s crucial to quickly identify and measure resistance. Antimicrobial Susceptibility Testing (AST) helps assess both the phenotypic and genotypic aspects of AMR. Unlike traditional methods like disc diffusion and broth dilution assays, new AST methods use molecular-based techniques (DNA and RNA-based) to detect resistance genes and their alterations. These advanced methods require sophisticated bioinformatics and large databases of resistance markers.

Broad-Spectrum Genomics AST
In diagnostics, there’s a shift from focusing on specific genes to using genomic techniques for identifying bacterial species and antibiotic resistance. Whole-genome sequencing (WGS) allows us to trace all AMR-related genes, providing a comprehensive view of resistance factors in a bacterial cell. Given the rapid increase in bacterial resistance compared to new drug development, it’s crucial for governments, industries, and research organisations to collaborate and promote innovation in AMR combat tools.

Novel Solutions Outside Traditional Development Pathways
The WHO’s 2020 pipeline report includes a comprehensive evaluation of non-traditional antibacterial drugs. It lists 27 emerging treatments, such as bacteriophages, antibodies, and therapies that enhance the patient’s immune system to combat bacteria.

Immuno-Antibiotics as an Alternative
Understanding how antibiotics interact with the immune system can lead to better treatments and slower development of resistance. For example, a study by Volk et al. found that combining β-lactam adjunctive therapy with standard antibiotics increased certain immune responses in patients with MRSA. While past attempts to develop a Staphylococcus aureus vaccine have failed, new therapies that combine immune response factors with traditional treatments show promise.
Recent innovations include dual-acting immuno-antibiotics (DAIAs), which target specific bacterial pathways like the MEP (methyl-D-erythritol phosphate) pathway of isoprenoid biosynthesis and riboflavin biosynthesis. These pathways are essential for bacteria but not found in humans, making them ideal targets for new antibiotics.

SOS Response Mechanism: A Critical Drug Target in Restraining AMR
The SOS response is a DNA repair process activated by DNA damage and oxidative stress. Emerging evidence suggests that targeting components of the SOS response, such as RecA and LexA, along with efflux pump inhibitors (EPIs), can prevent the development of antibiotic resistance. These inhibitors can enhance the effectiveness of bactericidal antibiotics, especially when used at sub-lethal concentrations.
By understanding and addressing these mechanisms and strategies, we can develop more effective ways to fight antibiotic resistance.
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Bacteriophage Therapy: A Key Direction in Combating Antibiotic Resistance
Imbalances in our microbiome can lead to illness. Studies on how bacteriophages (viruses that infect bacteria) interact with the human immune system are in their early stages. Much of what we know comes from phage therapy, which uses lytic phages to treat bacterial infections, and phage vaccines, which involve engineered phages for biotechnology applications. Despite extensive research on other microbiome components, our understanding of the human phageome (the collection of bacteriophages in our bodies) remains limited.

Computational Resources in Managing Antibiotic Resistance
Advanced computational tools are crucial in the search for new drugs to manage antibiotic resistance. Numerous methods have been developed to identify AR genes, mutations, and genomes, many of which rely on similarity-search tools like BLAST and HMMER.

Key Takeaways
Addressing AMR requires more than just discovering new antibiotics. It involves developing strategies to prevent the emergence of resistance and restore the effectiveness of existing antibiotics. Some of these new strategies include:
• Preventing Resistance: Implementing measures to limit or avoid the development of resistance to current antibiotics.
• Innovative Approaches: Encouraging the adoption of novel methods to combat resistance, such as bacteriophage therapy and immuno-antibiotics.
• Global Effort: A collaborative approach involving individuals, health professionals, policymakers, governments, and industries at both national and international levels.
Understanding the interactions between antibiotics and the immune system can lead to improved treatments and slower development of resistance. For example, dual-acting immuno-antibiotics (DAIAs) target specific bacterial pathways not found in humans, making them effective and safe. Targeting biochemical resistance pathways, including the inhibition of the SOS response and hydrogen sulfide production, presents new avenues for combating resistance.
Phage therapy, which uses bacteriophages to target and destroy antibiotic-resistant bacteria, is an emerging strategy. This approach, along with phage vaccines and engineered phages, offers a promising alternative to traditional antibiotics.
Combating antibiotic resistance requires a comprehensive strategy that involves:
• Individuals: Using antibiotics responsibly and maintaining good hygiene.
• Health Professionals: Implementing robust infection prevention and control practices.
• Policymakers: Developing and enforcing policies to regulate antibiotic use and promote research.
• Governments and Industries: Investing in the development of new drugs, diagnostics, and treatments.
By adopting a multidisciplinary and collaborative approach, we can effectively address the global threat of antibiotic resistance. Prevention and innovation are key to ensuring the continued effectiveness of antibiotics and safeguarding public health.

(The authors are from the Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi.)