Growing in a biofilm, or a layer of cells, allows bacteria to withstand antibiotic penetration. Biofilms can grow on catheters, pacemakers, joint prostheses, dentures, contact lenses, prosthetic heart valves, and implants. Growing in a biofilm, or a layer of cells, allows bacteria to withstand antibiotic penetration. Biofilms can grow on catheters, pacemakers, joint prostheses, dentures, contact lenses, prosthetic heart valves, and implants.
Outer layer of Gram-negative bacteria
Gram-negative bacteria are naturally resistant to various drugs that affect Gram-positive species due to their bilayer, outer membrane that is impenetrable to many drugs.
Return on investment
Low success rate of candidate molecules in combination with lesser return on investment are major challenges.
Timelines
It can take 10-15 years between initial molecule discovery to having a viable antibiotic reach the market.
Figure 3. Factors that can confound antimicrobial development.
Long-term survival of bacteria in the host, often asymptomatically, can lead to reactivation and reinfection. These long-surviving bacteria are called “persister bacteria.” Stringent response is a mechanism through which bacteria counter extreme starvation, which is thought to contribute to the development of persistent infection. Inhibiting this process could lead to greater bacterial susceptibility to antibiotics.
Bacterial vaccines
Preventing bacterial infections through vaccines leads to decreased antibiotic consumption and is likely to help with antibiotic resistance. A 2021 WHO report provided details of >60 and >90 vaccines in clinical and preclinical development, respectively.
Antimicrobial peptides
Antimicrobial peptides are gaining popularity as alternatives to small-molecule antibiotics. They are typically short (<100 amino acids) peptides with a broad spectrum of antimicrobial activity. According to the Antimicrobial Peptide Database, there are over 3,000 antimicrobial peptides as of November 2022.
Glycopeptides
Glycopeptides display antibacterial activity primarily against Gram-positive bacteria by inhibiting cell wall biosynthesis. Commonly used drugs in this group are vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin, but many new options are being developed, studied, and optimized.
Lipopeptides and lipoglycopeptides
Daptomycin is the only lipopeptide currently used against Gram-positive bacteria and functions by disrupting the bacterial cell membrane. The antibacterial effect observed appears dependent on the presence of and binding with calcium. Due to their large size, they are poorly absorbed when taken orally and tend to be administered intravenously.
Bacteriophages
Bacteriophages are viruses capable of infecting the bacteria cell and killing them by injecting viral DNA. The virus replicates within the cell and causes cell lysis as the replicas are released to find a new bacterial cell to infect. However, challenges still must be addressed to make bacteriophage therapy more viable, including poor in vivo efficacy for targeting bacterial species in the gut following oral administration.
Used together with antibiotics for drug delivery and wound healing. Hydrogels act in situ while being exposed to bodily cells and fluids to enable diffusible or gel-bound antibiotic agents such as antimicrobial peptides to be administered.
Nanoparticles
The small size of nanoparticles makes it easy for them to deliver drugs effectively. Surface modification can be used to tailor them for specific targets and locations, and the surface chemistry and composition control the timing of activity, drug release, and duration of action.
Composites
Composites use multiple materials together and are used for medical devices such as dental implants. The variety of materials capable of exerting antimicrobial activity have proven efficacy in both treating and preventing infection and transmission.
Films or coatings
Reducing the ability of medical devices to transmit infection would be an effective way to improve the health and survival of hospital patients. The ability to harness UV or visible light and generate reactive oxygen species that prevent microorganisms from adhering are two examples of effective films and coatings.
Scaffolds and implants
Useful for wound and bone healing, these typically have a high surface area-to-volume ratio and are more persistent than hydrogels. Implants with cationic polymers, copper nanoparticles, or nitric oxide-releasing agents have shown promising efficacy.
Figure 4. Materials and solutions that can reduce antibiotic usage
