Mycobacteriophage putative GTPase-activating protein can potentiate antibiotics

Abstract

The soaring incidences of infection by antimicrobial resistant (AR) pathogens and shortage of effective antibiotics with new mechanisms of action have renewed interest in phage therapy. This scenario is exemplified by resistant tuberculosis (TB), caused by resistant Mycobacterium tuberculosis. Mycobacteriophage SWU1 A321_gp67 encodes a putative GTPase-activating protein. Mycobacterium smegmatis with gp67 overexpression showed changed colony formation and biofilm morphology and supports the efficacy of streptomycin and capreomycin against Mycobacterium. gp67 down-regulated the transcription of genes involved in cell wall and biofilm development. To our knowledge, this is the first report to show that phage protein in addition to lysin or recombination components can synergize with existing antibiotics. Phage components might represent a promising new clue for better antibiotic potentiators.

<p>Phage therapy as a renewed therapeutic approach to mycobacterial infections: a comprehensive review</p>

“…Moreover, SWU1gp39 increases the susceptibility of Mtb to various stresses including heat shock, H2O2, SDS, and low PH 41,93. On the other hand, a putative GTPase-activating protein (GAP) is encoded with mycobacteriophage SWU1 A321_gp67 94. The GAP superfamily comprises 6 subfamilies including Ras, Rho, Ran, Rab, Rheb, and ARF 95.…”

“…Gp67 is a mycobacteriophage SWU1 late-stage gene that could change colony formation and biofilm morphology and may play a role in the reproduction and release of the phage progeny 97. Gp67 can downregulate the transcription of various genes such as MSMEG_0235, MSMEG_6092, MSMEG_1876, and mmpL4b 94. These genes have multiple roles in biofilm formation, cell wall integrity, and development of colony morphology 98.…”

“…These genes have multiple roles in biofilm formation, cell wall integrity, and development of colony morphology 98. Moreover, gp67 can increase the susceptibility of Mtb against different antibiotics such as streptomycin and capreomycin via several procedures including (a) making changes in cell wall integrity and cell wall structure and (b) preventing and disrupting biofilm formation 94. In total, it can be concluded that SWU1gp39 and gp67 might be utilized as a broad-spectrum antibiotic adjuvant or potentiator and be included into the existing antibiotic regimen for better control and greater efficiency of anti-tuberculosis drugs (including isoniazid and rifampicin) in bacterial killing (Figure 7).…”