Abstract
Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the leading causes of human deaths due to a single infectious agent. M. tuberculosis infection of the host initiates a local inflammatory response, resulting in the production of a range of inflammatory factors at the site of infection. These inflammatory factors may come in direct contact with M. tuberculosis and immune cells to activate different signaling pathways. One such factor produced in excess during inflammation is a phospholipid compound, Platelet Activating Factor C-16 (PAF C-16). In this study, PAF C-16 was shown to have a direct inhibitory effect on the growth of Mycobacterium bovis BCG (M. bovis BCG) and Mycobacterium smegmatis (M. smegmatis) in a dose- and time-dependent manner. Use of a range of PAF C-16 structural analogs, including the precursor form Lyso-PAF, revealed that small modifications in the structure of PAF C-16 did not alter its mycobacterial growth inhibitory properties. Subsequent experiments suggested that the attachment of aliphatic carbon tail via ether bond to the glycerol backbone of PAF C-16 was likely to play a vital role in its growth inhibition ability against mycobacteria. Fluorescence microscopy and flow cytometry using Propidium iodide (PI) indicated that PAF C-16 treatment had a damaging effect on the cell membrane of M. bovis BCG and M. smegmatis. Furthermore, the growth inhibitory effect of PAF C-16 was partially mitigated by treatment with membrane-stabilizing agents, α-tocopherol and Tween-80, which further suggests that the growth inhibitory effect of PAF C-16 was mediated through bacterial cell membrane damage.
Highlights
Tuberculosis (TB) is an infectious disease, caused by the acid-fast bacillus, Mycobacterium tuberculosis
Treatment of M. smegmatis and M. bovis BCG with PAF C-16 (10, 25, 50, and 100 μg/ml) for 2 h resulted in a dose-dependent growth inhibition, as evident from the decrease in the number of surviving colony forming units (CFUs) when compared with PAF C-16 solvent control (10 μl ethanol/ml bacterial culture) (Figures 1A,B)
Similar results were obtained for M. bovis BCG where 50 μg/ml and 100 μg/ml PAF C-16 treatment on an average reduced the number of surviving CFUs by 66% and 88%, respectively, when compared to the number of CFUs from the solvent control (Figure 1B)
Summary
Tuberculosis (TB) is an infectious disease, caused by the acid-fast bacillus, Mycobacterium tuberculosis. The only preventive vaccine against TB is BCG, which is almost a century old and not effective in controlling the spread of M. tuberculosis infections in economically active adult humans, which comprises the major population of TB patients in developing countries (Sepulveda et al, 1992; Colditz et al, 1994; Aronson et al, 2004; Lahey and von Reyn, 2016) New challenges, such as cases of HIV-1 and M. tuberculosis co-infection (Daley et al, 1992), multidrug-resistant tuberculosis (MDR-TB) (Espinal et al, 2000), and extensively drug resistant tuberculosis (XDR-TB) (Jain and Mondal, 2008; Liu et al, 2011) have compounded the severity of the problem, and novel therapeutic interventions are required to control TB
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