Mar 3

Decoding Bacterial Resistance: How Our Medicines Are Being Outsmarted

Introduction

Antibiotics, when first discovered, were considered miracle drugs. We are now facing a significant challenge: bacterial resistance, where our “miracle” drugs cannot treat the previously susceptible infections. Superbugs are emerging, making some infections increasingly difficult to treat. Are we entering a post-antibiotic era where common infections could become deadly? This blog post explores how bacteria evolve and develop to resist our best defences and what actions we can take to address this growing threat. We begin with a simple outline of the generalised anatomy of a healthy bacterial cell.

The Bacterial Cell In 
A Nutshell

Bacteria are single-celled organisms, usually round (coccus), rod (bacillus), spiral or vibrio (comma-shaped). Knowing a little about the anatomy of bacteria is useful in understanding how antibiotics affect bacteria, allowing us to understand how they function, grow, and reproduce. It also can help us understand how bacteria can outsmart our first line of defence against infection. This is a simplified view and will assist in understanding the action of antibiotics and the ways bacteria can develop resistance to them.



  • Cell Wall: This protective outer layer surrounds the bacterium, providing structural support and preventing it from bursting.  Antibiotics like penicillin target the production of the cell wall.  

  • Cell Membrane: Located beneath the cell wall, the cell membrane controls what enters and exits the cell

  • Ribosomes: These are essential for protein synthesis, which is crucial for bacterial growth and survival. Antibiotics such as tetracyclines target ribosomes to disrupt the synthesis of proteins. 

  • DNA: Contains the genetic information necessary for bacterial function, reproduction, and stability. Another antibiotic, ((fluoro)quinolone), halts the uncoiling of the DNA, needed for reproduction and repair.


Some bacteria also have other components:

  •  Porins: Channels in the outer membrane allowing antibiotics to enter the cell.    

  • Efflux Pumps: Act like "tiny bouncers" that pump antibiotics out of the cell.      

  • Biofilms: Communities of bacteria encased in a slimy matrix, making it harder for antibiotics to penetrate the individual bacterial cell.


How Antibiotics Work

Antibiotics work by targeting essential processes within bacterial cells, such as cell wall synthesis, protein synthesis, and DNA replication. Many antibiotics are derived from natural sources, produced by bacteria themselves, to compete with one another – not necessarily of the same species.  More familiar examples of antibiotics are cited in these groups.

  • Beta-lactams, like penicillin, inhibit the production of a crucial component of bacterial cell walls, causing the bacteria to burst.

  • Tetracyclines, target ribosomes, which are essential for protein synthesis, disrupting bacterial growth and survival.

  • Cell wall synthesis inhibitors: Block the formation of the protective cell wall, causing the bacteria to burst. Examples include beta-lactams (penicillin and cephalosporins) and glycopeptides (vancomycin).

  • Cell membrane disruptors: Damage the cell membrane, leading to leakage of essential cell contents. For example, polymyxins (used in some multi-drug-resistant infections). 

  • Folate synthesis inhibitors: Prevent the production of folate, vital for bacterial growth. Examples given are sulphonamides (sulphur drugs).

  • DNA gyrase inhibitors: Stop the uncoiling of DNA necessary for reproduction and repair. DNA is present in all cells but coiled. It is required to be “straightened out” before it can be used by the cell.

  • RNA synthesis inhibitors: Block RNA production needed for protein synthesis, with examples like annamycin's (Clindamycin) and rifamycins.

  • Protein synthesis inhibitors: Disrupt protein synthesis within the cell machinery essential for growth. Examples include tetracyclines and macrolides.


    A little understanding of how bacteria function allows the appreciation of how bacteria can develop resistance to our antibiotics.

Mechanism Of Antibiotics 
Resistance

Bacteria can develop resistance through various mechanisms, including limiting antibiotic entry, inactivating the antibiotic, and modifying the antibiotic target within the bacterial cell.

Efflux Pumps: These act like tiny bouncers in the bacterial cell membrane, actively pumping antibiotics out of the cell, preventing them from reaching their target.

1. Limiting Antibiotic Entry.

  • Efflux Pumps: These act like tiny bouncers in the bacterial cell membrane, actively pumping antibiotics out of the cell, preventing them from reaching their target.

  • Porin Changes: Some bacteria have channels (porins) in their outer membranes that allow antibiotics to enter. Changes in the number or structure of these porins can reduce the amount, therefore the dosage, of antibiotic taken into the cell.

  • Biofilms: These are communities of bacteria encased in a slimy film making it harder for antibiotics to penetrate the individual bacterial cell.     
     

2. Inactivating the Antibiotic.

  • Enzymatic Destruction: Bacteria produce enzymes that can break down antibiotics. A classic example is beta-lactamase, which inactivates penicillin-like drugs.

  • Chemical Modification: Some bacteria can add extra groups to the chemical structure of antibiotics, preventing them from working as they should.


3. Modifying the Antibiotic Target.

  • Target Mutation: Antibiotics bind to specific targets within bacteria. Mutations in the genes in these targets can change their shape, preventing the antibiotic from binding to it correctly.

  • Target Bypass: Some bacteria can find alternative pathways or targets that the antibiotic doesn't affect, allowing them to continue with essential processes even in the presence of the antibiotic

4. Other Mechanisms

  • Reduced Metabolism: Some antibiotics work by disrupting the metabolism of the bacteria. Bacteria in a dormant or slow-growing state may be less susceptible to these particular antibiotics.

  • Increased Production of Target: In some cases, bacteria can increase the production of the antibiotic's target, making it harder for the drug to bind to all of them and have a significant effect.

The Evolution And 
Spread Of Resistance

Resistance evolves through spontaneous DNA mutations or rearrangements (de novo innovation) and conjugation, transduction, or transformation (horizontal gene transfer).

Horizontal gene transfer allows bacteria to share resistance mechanisms, even between different species.

Antibiotics create selection pressure, favouring the survival and reproduction of resistant bacteria.

While resistance mechanisms can be costly to the bacterium, if the benefits of surviving antibiotics outweigh the costs, the resistant bacteria will dominate within a population.

SUPERBUGS

Superbugs are microorganisms resistant to multiple antibiotics. Infections caused by these superbugs are harder to treat due to multiple resistances, leading to longer illnesses and increased mortality.

  • Methicillin-resistant Staphylococcus aureus (MRSA): is resistant to methicillin and related antibiotics, causing skin infections, pneumonia, and bloodstream infections.

  • Carbapenem-resistant Enterobacterales (CRE): Resistant to carbapenems, a class of “last-resort antibiotics”, causing urinary tract infections and pneumonia.

  • Multidrug-resistant Pseudomonas aeruginosa: Resistant to multiple antibiotics, causing pneumonia and bloodstream infections. It is especially dangerous in those with weakened immune systems.

  • Drug-resistant Neisseria gonorrhoeae: This bacterium causes gonorrhoea, a sexually transmitted infection that is becoming increasingly difficult to treat due to antibiotic resistance.

FIGHTING BACK: WHAT CAN BE DONE?

Addressing antibiotic resistance requires a multifaceted approach. Using antibiotics differently, using a combination of antibiotics with different actions on the bacterial cell, or utilising the specific actions some antibiotics have. Antibiotic stewardship promotes responsible antibiotic use in human and animal health to slow down resistance development. Science can therefore work towards developing new antibiotics, new ways of using known antibiotics, or alternatives to these wonder drugs. What can we do:

  • Combination Therapy: Combine existing antibiotics to overcome bacterial resistance mechanisms.

  • Resistance-Breakers: Develop drugs that specifically disable resistance mechanisms, such as efflux pump inhibitors, to stop the bacterium from being able to pump antibiotics out of its cell.

  • Antimicrobial Peptides: Utilise naturally occurring substances with antibacterial activity that are less prone to resistance development.

  • Phage Therapy: Use viruses (bacteriophages) that specifically infect and kill bacteria.

  • Global Collaboration: Foster international cooperation to share knowledge, resources, and develop effective strategies to fight resistance and develop new therapies.

  • Rapid Diagnostics: Develop rapid diagnostic tests to quickly identify the cause of infections and determine antibiotic susceptibility.

  • Reviving Old Antibiotics: Some older antibiotics, for example, polymyxins, fell out of favour due to toxicity concerns, but with modifications and new delivery methods, they could be repurposed against resistant strains.

  • CRISPR-Cas Systems: This gene-editing technology could be used to target and destroy specific resistance genes in bacteria, making them susceptible to antibiotics again.

  • Infection Prevention: Implement effective infection control measures in aged care and other healthcare settings. By reducing the number of infections in a facility, we would reduce the need for antibiotics in the first place. AMS has shown us that the prolific use of antibiotics is often unnecessary and with better diagnoses we can treat infections more specifically.


CONCLUSION

Antibiotic resistance is a serious and growing threat, potentially leading to a post-antibiotic era in the not-too-distant future. Combating this challenge requires a concerted effort. By using antibiotics wisely, practising good hygiene, and supporting research, we can all play a role in preserving the effectiveness of these life-saving drugs. What steps can we take individually and collectively to ensure that antibiotics remain effective for future generations? Dive deeper into this critical topic by exploring our related articles or subscribing to our newsletter for the latest updates.