Cyclic Peptide [R4W4] in Improving the Ability of First-Line Antibiotics to Inhibit Mycobacterium tuberculosis Inside in vitro Human Granulomas

Abstract

Tuberculosis (TB) is currently one of the leading causes of global mortality. Medical non-compliance due to the length of the treatment and antibiotic side effects has led to the emergence of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (M. tb) that are difficult to treat. A current therapeutic strategy attempting to circumvent this issue aims to enhance drug delivery to reduce the duration of the antibiotic regimen or dosage of first-line antibiotics. One such agent that may help is cyclic peptide [R 4 W 4 ], as it has been shown to have antibacterial properties (in combination with tetracycline) against methicillin-resistant Staphylococcus aureus (MRSA) in the past. The objective of this study is to test cyclic peptide [R 4 W 4 ] both alone and in combination with current first-line antibiotics (either isoniazid or pyrazinamide) to study the effects of inhibition of M. tb inside in vitro human granulomas. Results from our studies indicate that [R 4 W 4 ] is efficacious in controlling M. tb infection in the granulomas and has enhanced inhibitory effects in the presence of first-line antibiotics.

Assessment of Experimental Techniques That Facilitate Human Granuloma Formation in an In Vitro System: A Systematic Review

“…A majority of the studies were focused on mycobacteria antigens, including several mycobacterial strains such as M. tb H37Rv [ 5 , 22 , 27 , 28 , 38 , 39 , 43 , 44 , 45 , 47 , 49 , 50 , 55 , 66 , 71 , 72 , 73 , 74 , 75 , 76 ], M. tb Erdmann [ 63 , 65 , 77 , 78 ], and species such as M. leprae [ 12 , 79 ], M. abscessus [ 48 ] as well as BCG [ 24 , 29 , 30 , 56 , 57 , 62 , 69 , 80 ] and PPD [ 23 , 54 , 59 , 61 ]. Others used antigens of other infectious species such as Schistosoma [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 58 ] or Candida [ 2 , 26 , 42 , 81 ].…”

Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

“…The activity was determined against infected peripheral blood mononuclear cells (PBMCs) by quantification of the intracellular survival of the bacteria. 54 In this study, a library of 24 cyclic peptides was rationally designed based on the [R n W n ] sequence as the model scaffold to study the impact of the hydrophilic/hydrophobic ratio, charge, and ring size on antibacterial activity. This study assisted in establishing a structure−activity relationship (SAR) to understand further the role of R and W residues and the cationic/hydrophobic ratio on antibacterial activity and other essential properties.…”

“…The use of [R 4 W 4 ], along with first-line antituberculosis medications, reduced the side effects of antibiotics and improved the immune responses to get rid of the active Mycobacterium tuberculosis (Edman strain) infection. The activity was determined against infected peripheral blood mononuclear cells (PBMCs) by quantification of the intracellular survival of the bacteria …”

“…The activity was determined against infected peripheral blood mononuclear cells (PBMCs) by quantification of the intracellular survival of the bacteria. 54 …”

Combination of Amphiphilic Cyclic Peptide [R4W4] and Levofloxacin against Multidrug-Resistant Bacteria

“…It was concluded that [R 4 W 4 ], [R 3 W 4 ], and [R 4 W 3 ] peptides showed similar potency with a MIC value of ~2.97 µg/mL (~2.1 µM) [24]. Furthermore, a combination of [R 4 W 4 ] alone and in combination with current first-line antibiotics (isoniazid or pyrazinamide) showed efficacious in treating Mycobacterium tuberculosis (M. tb) inside human granulomas [25].…”