Molecular Mechanisms of Antibiotic Resistance: Unlocking the Secrets for Future Therapies - The Global Antibiotics Resistance Foundation

Antibiotic resistance is, as we have discovered in our previous blogs, one of the most
pressing challenges in modern medicine. It is one of the top global public health and
development threats. Bacterial AMR was estimated to be directly responsible for 1.27
million global deaths in 2019 and contributed to 4.95 million deaths. The increasing
prevalence of resistant bacteria threatens the effectiveness of antibiotics, which have been
the cornerstone of treating bacterial infections for decades.

Understanding the intricate molecular processes behind antibiotic resistance enables
scientists to develop targeted therapies that can overcome these resistance mechanisms
and restore the effectiveness of antibiotics. This paves the way for innovative treatment
approaches, such as developing new drugs or combination therapies that can bypass or
disrupt the resistance mechanisms.

Key Mechanisms of Antibiotic Resistance

To tackle antibiotic resistance effectively, we need to delve into the molecular
mechanisms that bacteria use to evade the effects of antibiotics. Here are some of the
primary mechanisms:

1.Enzymatic Degradation or Modification

○ β-lactamases: These enzymes, produced by bacteria, can hydrolyse the
β-lactam ring found in penicillins and cephalosporins, rendering these
antibiotics ineffective. Some beta-lactamases are encoded on mobile
genetic elements (eg, plasmids); others are encoded on chromosomes.
Notable types include extended-spectrum β-lactamases (ESBLs) and
carbapenemases, which target a wide range of β-lactam antibiotics.
○ Aminoglycoside-modifying enzymes:
These alter aminoglycosides through processes such as phosphorylation, adenylation,
enzymes or acetylation. These modifications prevent aminoglycosides from binding
to bacterial ribosomes, which is essential for their antibacterial activity. The
number of aminoglycoside-modifying enzymes identified to date as well as
the genetic environments where the coding genes are located is impressive
and there is virtually no bacteria that is unable to support enzymatic
resistance to aminoglycosides.

2.Target Site Alterations

○ Methicillin-resistant Staphylococcus aureus (MRSA): MRSA alters
penicillin-binding proteins (PBPs), which are the target sites for β-lactam
antibiotics. These altered PBPs have a reduced affinity for the antibiotics,
leading to resistance. MRSA most often causes skin infections but it can
also cause serious infections in your lungs, heart and bloodstream.
MRSA used to spread mostly in healthcare settings — among people in
hospitals or long-term care facilities (healthcare-acquired MRSA
HA-MRSA).
○ Vancomycin-resistant Enterococci (VRE): Enterococci are facultative
anaerobic gram-positive cocci that are normally commensal organisms of
the human gastrointestinal tract. VRE modifies the D-Ala-D-Ala terminus
of the peptidoglycan precursor, which is the binding site for vancomycin.
This modification prevents vancomycin from inhibiting cell wall synthesis.

3.Efflux Pumps

○ Efflux pumps are transport proteins involved in the extrusion of toxic
substrates (including virtually all classes of clinically relevant antibiotics)
from within cells into the external environment.
○ Bacteria use efflux pumps to expel antibiotics from their cells before the
drugs can reach their targets. Multidrug efflux pumps can confer resistance
to a wide range of antibiotics, including tetracyclines, quinolones, and
macrolides.

4.Reduced Permeability

○ Some bacteria decrease the permeability of their cell membranes to prevent
antibiotics from entering the cell. This mechanism is particularly effective
against antibiotics that rely on porin channels to enter Gram-negative
bacteria.

Innovative Approaches to Combat Antibiotic Resistance

With a deeper understanding of these resistance mechanisms, researchers are developing
innovative strategies to combat antibiotic-resistant bacteria. Here are a few promising
approaches:

1.Novel Antibiotics

○ Lipopeptides: These new classes of antibiotics, such as daptomycin, target
the bacterial cell membrane, causing rapid depolarisation and cell death.
Their unique mechanism of action helps them evade traditional resistance
mechanisms.
○ Antimicrobial peptides (AMPs): AMPs are short proteins that can disrupt
bacterial membranes, and they hold potential as new therapeutic agents due
to their broad-spectrum activity and lower likelihood of resistance
development.

2.Combination Therapies

○ Using combinations of antibiotics can help prevent the development of
resistance by attacking bacteria through multiple mechanisms
simultaneously. For example, β-lactam antibiotics can be combined with
β-lactamase inhibitors to protect the antibiotic from degradation.
○ Synergistic combinations: Researchers are exploring combinations of
antibiotics with non-antibiotic agents, such as efflux pump inhibitors, to
enhance the efficacy of existing drugs. For example, C + D-ciprofloxacin +
daptomycin; C + V- ciprofloxacin + vancomycin; D + T-daptomycin +
tobramycin; T + V- tobramycin + vancomycin. Antibiotics in all four
combinations showed synergy in the case of S48isolate of Staphylococcus
aureus.

3.Phage Therapy

○ Bacteriophages, or phages, are viruses that specifically infect bacteria.
Phage therapy involves using these viruses to target and kill
antibiotic-resistant bacteria. This approach is gaining attention as a
potential alternative to traditional antibiotics.

4.CRISPR-Cas Systems

○ CRISPR-Cas gene-editing technology can be used to target and disable
resistance genes in bacteria, restoring their susceptibility to antibiotics. This
method offers a highly specific approach to overcoming resistance.

The Road Ahead

Antibiotic resistance remains a formidable challenge in modern medicine, posing a severe
threat to global health by diminishing the efficacy of drugs that have long been the
mainstay of bacterial infection treatment. The high mortality rate associated with resistant
infections highlights the urgent need for innovative solutions. By comprehending the
intricate molecular mechanisms underlying antibiotic resistance, scientists can devise
targeted strategies to counteract these defences and restore the potency of existing
antibiotics.

Key resistance mechanisms include enzymatic degradation, target site alterations, efflux
pumps, and reduced permeability, each offering unique challenges to overcome. Novel
antibiotics such as lipopeptides and antimicrobial peptides, combination therapies that
leverage synergistic effects, and ground breaking approaches like phage therapy and
CRISPR-Cas gene editing represent promising avenues in this fight.

Continued research and investment are critical to developing these innovative therapies
and staying ahead in this battle against resistant bacteria. By leveraging our expanding
knowledge of molecular resistance mechanisms, we can create effective treatment
options, ensuring antibiotics remain powerful tools in combating bacterial infections. The
road ahead is challenging, but with dedicated efforts, the future of antibiotic therapy
looks hopeful.

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