Phage therapy as a renewed therapeutic approach to mycobacterial infections: a comprehensive review

Figures & data

Figure 1 Steps involved in phage mediated Mycobacterium tuberculosis lysis using Mycobacterium smegmatis.

Table 1 The list of mycobacteriophages used against Mycobacteria infections: targets, mechanisms, and results of phage therapy

Phages	Targets	Mechanisms	Results of phages therapy
DS-6A	Mycobacterium tuberculosis, Mycobacterium ulcerans	Plaque formation on mycobacteria belonging to the MTBC	Reduction of infection in liver, spleen and lung lesions. Complete Elimination of Mtb from infections sites. Improvement of lesions (infection reduction) in lungs, spleen and livers in BU.
TM4	Mycobacterium tuberculosis, Mycobacterium avium	Unknown Lysing and killing M. avium inside mononuclear cells such as macrophages and monocytes.	Liposomal-delivered mycobacteriophage TM4 could have direct access to intracellular Mtb, finally destroying the intracellular pathogen. Treatment of M. avium infected macrophages with TM4 contributed to a considerable decrease in the number of M. avium bacilli.
D29	Mycobacterium tuberculosis, Mycobacterium ulcerans	Lysin A hydrolyzing peptidoglycan of Mtb. Lysin B disseminating mycolic acid from the peptidoglycans in Mtb cell wall. Inducing a cellular infiltrate of a macrophagic/lymphocytic profile in BU. D29 having an extensive lytic activity against mycolactone-producing M. ulcerans. D29 increasing the levels of TNF, IFN-γ, and IL-10. D29 resulting in the increase and maintenance of a local mononuclear inflammatory response to M. ulcerans.	Complete Elimination of Mtb from infections sites. Mycobacterium ulcerans lysed and eradicated due to the lytic activity of phage. Reduction of the proliferation of the mycolactone-producing M. ulcerans.
T7	Mycobacterium tuberculosis	Gp2 binding to the β subunit of RNA polymerase and preventing transcription by inhibition initialization of the nascent RNA transcript. Gp2 prevents the enzymatic activity of Mtb RNA polymerase.	T7 effectively kills the Mtb.
P4	Mycobacterium tuberculosis	Bacteriophage P4 capsid protein Psu inhibiting ATPase and translocase activities of the Rho proteins in two ways: I) The binding of Psu to Rho proteins causing Rho proteins to be unable to terminate with a Rho-dependent terminator. II) Psu via direct interaction with Rho preteens preventing the release of RNA from a stalled elongation complex.	P4 can effectively kill the Mtb.
PDRPv	Mycobacterium tuberculosis	Unknown	Phage PDRPv showed a lytic activity against Mtb.
BTCU-1	Mycobacterium tuberculosis	BTCU-1 encoding two endolysins as follows: I) The cleavage of the peptidoglycan in the cell wall of mycobacteria is done by lysA. II) The release of free mycolic acid from the mycolylarabinogalactan bond is carried out by lysB.	LysA and lysB have antimicrobial activity and make significant changes in the cell shape of Mtb. These endolysins eradicate most of Mtb during the course of their life cycle.
Bo4	Mycobacterium tuberculosis, NTM, Mycobacterium bovis	Bo4 has antimicrobial activity and could lyse and effectively halts the growth of Mtb	A lytic phage possibly eradicates Mtb in infectious sites.
SWU1	Mycobacterium tuberculosis	Inhibiting the lipid metabolism and preventing the usual production of long-chain fatty acids. Increasing the cell wall permeability and potentiating the efficiency of multiple antibiotics. Increasing the susceptibility of Mtb against heat shock, H2O2, SDS, and low PH. Changing colony formation and biofilm morphology.	SWU1gp39 and gp67 might be included as a broad-spectrum antibiotic adjuvant or potentiator.
GR-21/T	Mycobacterium tuberculosis	Unknown	Reduction of infection in liver, spleen and lung lesions.
My-327	Mycobacterium tuberculosis	Unknown	Reduction of infection in liver, spleen and lung lesions.
Ms6	Mycobacterium smegmatis, Mycobacterium tuberculosis Mycobacterium bovis, BCG	Similar to the phage D29, Lysin A hydrolyzing peptidoglycan of Mtb cell wall. LysB encoding a protein with lipolytic activity that hydrolyzes a wide spectrum of fatty acid esters in Mtb. Cleavage of ester bond among arabinogalactan and mAGP. Cleavage of the ester bond between trehalose and mycolic acids in TDM.	LysA and lysB have antimicrobial activity, and these endolysins eradicate most of Mtb during the course of their life cycle.
Bxz2	Mycobacterium ulcerans	Unknown	Bxz2 has the highest lytic activity against Mycobacterium ulcerans.

Abbreviations: BCG, Bacille Calmette Guérin; MTBC, Mycobacterium tuberculosis complex; Mtb, Mycobacterium tuberculosis; BU, Buruli Ulcer; TNF-α, Tumor necrosis factor alpha; IFN-γ, Interferon gamma; NTM, Non-tuberculosis mycobacterium; mAGP, Mycolyl-arabinogalactan-peptidoglycan; TDM, Trehalose 6,6′-dimycolate.

Figure 2 Steps involved in phage TM4 mediated Mycobacterium tuberculosis lysis using liposome.

Figure 3 Overview of phage D29 mediated Mycobacterium tuberculosis lysis.

Figure 4 Steps involved in phage T7 mediated Mycobacterium tuberculosis lysis.

Figure 5 Overview of phage P4 mediated Mycobacterium tuberculosis lysis.

Figure 6 Overview of phage BTCU-1 mediated Mycobacterium tuberculosis lysis.

Figure 7 Overview of phage SWU1 mediated Mycobacterium tuberculosis lysis.

Figure 8 Overview of phage MS6 mediated Mycobacterium tuberculosis lysis.