Phage vs TB: A Biblical Battle

The struggle against tuberculosis (TB) is a long uphill battle. We need serious therapeutic help right now. Some recent WHO statistics suggest that upward of a quarter to a third of our global population may be latently infected with the bacterial source of active TB, Mycobacterium tuberculosis. Multi-drug (MDR-MTB) and extreme multi-drug resistant (XTR-MTB) have emerged as a global health crisis, with no clear end in sight. Yet, based on a new study in Scientific Reports, we may have found our one salvation and its not traditional antibiotics. We may be able to actually turn the table on M. tuberculosis by using “bacterial virus”, i.e. bacteriophages, to do our dirty work.

TB-like symptoms are described in writings dating back to the ancient Greeks. A more contemporary story of the suffering TB inflicts on patients received a Pulitzer Prize for in depth coverage of Haitian TB patients. Mountains Beyond Mountains describes in minute details the effects of TB treatment or the lack of TB treatment has on patients and the impact a caring physician like Dr. Paul Farmer can have on cures or relapses. Sadly in the years since this book reported on the dire situation in poverty-stricken Haiti, TB has become even more difficult to treat or cure.

Bacteria in the genus Mycobacterium are notoriously difficult to treat with routine antibiotics. The unique and distinguishing characteristics of Mycobacterium, an impervious hydrophobic cell wall and extremely slow growth curves make traditional front line antibiotics ineffective. This uniqueness is also an opportunity to target these novel synthetic pathways. Isoniazid (INH) targets the cell wall builder, disrupting the wall thickness and structure. Yet M. tuberculosis is able to rapidly mutate this builder enzyme and evade the drug effects resulting in resistant strains.

Current Standard of Care for patients requires a minimum of 6 months of antibiotic cocktails, rotating as resistance arises or patient tolerance declines. Perceived cures may end up in reactivation disease, which is even more drug resistant and deadly. Detection and surveillance of TB in susceptible populations is confounded by infections with other Mycobacterium species endemic to TB hotspot regions, such as the M. africanum species. Regional subspecies of TB are frequently missed when clinicians rely on rapid TB tests allowing potentially infectious individuals to remain untreated and thus a serious infectious threat to others.

With increasing numbers of confirmed cases, increasing drug resistance and decreasing patient compliance, TB – “consumption” if you read English literature – is becoming more threatening to general populations. A new report published in The Lancet is increasing awareness of prisoner TB populations as a driving force for communal spread of TB. Prison screening methods and lack of prison patient monitoring coupled with early release and liberal visitation policies expose entire communities to this ancient threat. Novel modes of therapy are desperately needed, where treatment times can be reduced to days or weeks and resistance can be moderated. One such idea, the use of bacterial phages, to potentiate traditional antibiotics by weakening individual bacteria is gaining hold. Phage Therapy, as it is currently called, has been used clinically worldwide for control of other resistant bacteria with mixed results. Isolation of specific phages for resistant bacteria requires significant effort and screening methods are laborious. However, these bacterial viruses can be packaged for oral administration, which is a huge leap forward over injectable or IV only antibiotics.

Now the most promising news for TB clinicians, a group of Chinese pharmaceutical researchers has isolated a very specific phage direct against M. tuberculosis cell wall integrity. Mycobacteriophage SWU1 gp39 targets not only cell wall permeability but bioenergics and lipid metabolism of the bacteria are negatively affected as well; add in rounds of traditional antibiotics and BAM! TB is on the ropes.

Maybe it is just luck this phage was isolated and appears to have great promise to supplement current SOC. The specificity and mode of action however make this find truly impressive. Our hope is that now we have isolated one phage, other virulent lytic M. tuberculosis phages can be identified and added to this arsenal, keeping TB guessing what comes next and resistance at bay. Clinical trials and approvals cannot come soon enough.

Li Q, et al. (2016) Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics

against Mycobacterium via altering the cell wall permeability. Sci Rep 6:28701.

doi:10.1038/srep28701