Chapter 149
Defeating Infectious Agents — 13
Avery different approach, relying on not AI but traditional structural biology to inform drug design, led to discovery of cresomycin, which has very broad action against several resistant strains of bacteria. A vaccine directed against methicillin-resistant S. aureus represents yet another potential approach. So does the first “smart” antibiotic developed that spares the gut microbiome, lolamicin. It works against the genome sequence of disease-causing bacteria and doesn’t disturb the friendly, non-disease-causing bacteria that inhabit our gut. Lolamicin is a Gram-negative-specific antibiotic that was shown to be active against 130 multidrug-resistant clinical isolates, and effective in multiple mouse models. Many of these efforts have led to clinical trials with hopes they will prove effective and safe as well as help enrich our armamentarium in the battle against resistant microbes.
Besides AI and structure-based discovery, bacteriophage (phage) therapy offers another highway to outflanking microbial resistance. These are viruses that are the natural predators of bacteria with a representative structure (fig. 10.3) from one of the three families (Siphoviridae, shown; Myoviridae; and Podoviridae). The capsid holds and protects the phage’s DNA. The tails help penetrate specific strains of bacteria. Once inside the bacteria cells, the phage hijacks its resources, rapidly proliferates, and explodes. With that destruction, the proliferation of new phages is released to infect more cells, which occurs exponentially. Bacteria are not defenseless against phages. They have multiple CRISPR-Cas endonucleases and more than one hundred newly discovered defense systems, and the phages have anti-CRISPR counter defenses.
Their abundance in nature is extraordinary, with about 1031 phages in the biosphere, the most abundant and diverse biological entity on the planet, with 1023 infections per second on a global scale. The history of phages is long, with their discovery dating to 1896, and their origins more than three billion years ago. Nevertheless, their therapeutic efficacy in combination with antibiotics or as solo therapy for infectious diseases has not been well established. Slowness in the field may be related to obstacles such as a bias against using a virus to treat infections, questions on patentability, and pessimistic expectations for regulatory approval.
Figure 10.3. Structure of a bacteriophage (phage). Adapted from Franklin Nobrega et al., “Targeting mechanisms of tailed bacteriophages,” Nature Reviews Microbiology 16, no. 12 (December 2018): 760–73, https://doi.org/10.1038/s41579-018-0070-8.
That’s changing now. With a series of successful case reports for treating life-threatening conditions with multidrug resistance, interest is beginning to soar in recent years, with many more ongoing clinical trials tackling highly challenging bacterial infections that are resistant to antibiotics: Staphylococcus aureus for diabetic foot ulcers, chronic sinusitis, resistant ear infections (otitis media), sepsis, and endocarditis; Pseudomonas aeruginosa for lung infection, otitis media, artificial joint infection, osteomyelitis, cystic fibrosis bronchiectasis, and aortic grafts; Klebsiella pneumoniae (carbapenem-resistant) for artificial joint infection, gut colonization, and sepsis; Escherichia coli for urinary tract infections; and Acinetobacter baumannii for pneumonia. Of more than ninety clinical phage trials worldwide, about half are in the United States. Doctors can use the Center for Phage Applications and Therapeutics to find the right phage for the right patient. A compilation of one hundred consecutive cases of personalized phage therapy from a consortium of thirty-five hospitals in twelve countries demonstrated clinical improvement for over 70 percent of patients and eradication of the target bacteria in more than 60 percent. The best results were obtained with concomitant use of antibiotics, but interpretation is limited without a control group. Still, the potential for bacteriophages to aid the fight against drug-resistant bacteria is promising.