Since the discovery of Penicillin in 1928, the compound has been modified several times and other new drugs have been found that also exhibit antimicrobial effects. However, the bacteria against which these are used have evolved as well, developing resistance mechanisms to many of the antibiotics currently available. Mutations occur more regularly in bacterial cells compared to eukaryotic cells due to the lack of proof-reading ability from DNA polymerase. As a result, mutations can more readily arise that give resistance to antibiotics. These can quickly propagate through a population due to horizontal gene transfer; by conjugation, transformation, and transduction. Consequently, multi-drug resistant bacterial strains have been observed in increasing numbers over the years, with Pandrug resistant strains now emerging. It is clear a new approach is needed and one possible alternative lies with Bdellovibrio bacteriovorus.
B. bacteriovorus is a species of predatory bacteria, capable of infecting and destroying other bacterial cells. Bacterial cells can be classified by their cell wall, being either Gram positive or Gram negative. Gram positive cell walls comprise of a thick layer of peptidoglycan, whereas Gram negative cells have a thin peptidoglycan layer that is surrounded by an outer membrane. B. bacteriovorus can infect Gram negative cells as shown in Figure 1. They attach and infiltrate the periplasmic space, between the inner and outer membrane (Sockett, 2009), where they can kill the host cell in as little as 30 minutes. They can then replicate using the contents of the host, with progeny initiating the lysis of the host cell between 180-240 minutes later.
A study was carried out to determine how effective B. bacteriovorus was at regulating an antibiotic resistant infection in vivo (Willis et al., 2016). Antibiotic resistant Shigella flexneri strains were used to infect the hindbrain of Zebrafish larvae, and were subsequently treated with PBS as a control (Figure 2). This resulted with infection conditions worsening greatly over the next 48-hour period. However, when treated with B. bacteriovorus, the S. flexneri infection was reduced significantly, with the predatory bacteria also being largely eliminated 48 hours post-infection (hpi). This reflects the prey-dependant lifestyle that is needed for B. bacteriovorus to thrive, and is one of the factors that make it a possible alternative to antibiotics.
Due to B. bacteriovorus replication within a host bacterium, repeat doses are not required to clear an infection. Research shows that after a delay, leukocytes are recruited to clear B. bacteriovorus, giving it time to destroy the pathogenic bacteria (Willis et al., 2016). However, it was also found that in immunocompromised subjects with no leukocytes, that prolonged infection by the bacteria had no negative connotations on the subject’s survival. Another benefit is that when the host cells are lysed after B. bacteriovorus replication, the contents released are partly digested by predator enzymes. As a result, endotoxins (Lipopolysaccharides found on the bacterial cell surface) are not released, preventing side effects that can occur with antibiotic use (Haziot et al., 1996).
However, there are a number of shortcomings of B. bacterivorus that must still be considered as the possibility of use within humans is explored. Due to the fact that it can only infect Gram negative bacteria, the host is left open to infection by opportunistic Gram Positive pathogens such as Clostridium difficile. Also, although no pathogenesis has been observed in humans, the ability for this bacteria to pick up virulence genes must be investigated before its use as an antibiotic alternative.
Despite the promising results using B. bacteriovorus to treat bacterial infections, there is still much research needed before it can be utilised as an alternative to antibiotics. In the meantime, it is our social responsibility to ensure that our antibiotics remain effective until an alternative becomes available. If we do not, we risk going back to the ages before modern medicine.
HAZIOT, A., FERRERO, E., KONTGEN, F., HIJIYA, N., YAMAMOTO, S., SILVER, J., STEWART, C. L. & GOYERT, S. M. 1996. Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity, 4, 407-414.
SOCKETT, R. E. 2009. Predatory Lifestyle of Bdellovibrio bacteriovorus. Annual Review of Microbiology, 63, 523-539.
WILLIS, A. R., MOORE, C., MAZON-MOYA, M., KROKOWSKI, S., LAMBERT, C., TILL, R., MOSTOWY, S. and SOCKETT, R. E. 2016. Injections of Predatory Bacteria Work Alongside Host Immune Cells to Treat Shigella Infection in Zebrafish Larvae. Current Biology, 26, 3343-3351.