Design and synthesis of acyldepsipeptide-1 analogues: antibacterial activity and cytotoxicity screening

Acyldepsipeptides (ADEPs) are receiving more attention as prospective antimicrobial agents due to their unique mode of action and chemical properties. However, their therapeutic potential is limited by their poor pharmacokinetic properties. Chemical modifications have been successful in improving the biocompatibility and bioavailability of ADEPs. In the current study, ADEP1 was modified by introducing a disulphide linkage, replacement of the octa-2,4,6-trienoic acid (OTEA) with either adamantane (Ada) or palmitic acid (Pal), and lastly, comparing the use of D versus L amino acids. The antibacterial effects of the ADEP1 analogues were investigated in Gram-positive and Gram-negative strains using agar well diffusion and microdilution assays. Cytotoxicity was evaluated in human embryonic kidney (HEK)-293 and colon cancer (Caco-2) cells by the MTS assay. Using solid phase peptide synthesis (SPPS), the percentage yield of the synthetic peptides was increased to > 37% with > 96% purity

Acyldepsipeptide analogues: A future generation antibiotics for Tuberculosis treatment

Acyldepsipeptides (ADEPs) are a new class of emerging antimicrobial peptides (AMPs), which are currently explored for treatment of pathogenic infections, including tuberculosis (TB). These cyclic hydrophobic peptides have a unique bacterial target to the conventional anti-TB drugs, and present a therapeutic window to overcome Mycobacterium Tuberculosis (M. tb) drug resistance. ADEPs exerts their antibacterial activity on M. tb strains through activation of the protein homeostatic regulatory protease, the caseinolytic protease (ClpP1P2). ClpP1P2 is normally regulated and activated by the ClpP-ATPases to degrade misfolded and toxic peptides and/or short proteins. ADEPs bind and dysregulate all the homeostatic capabilities of ClpP1P2 while inducing non-selective proteolysis. The uncontrolled proteolysis leads to M. tb cell death within the host

Prolonged SARS-CoV-2 RNA shedding in a young man recovering from traumatic pneumothorax

We describe a case of prolonged SARS-CoV-2 RNA shedding in an HIV-negative 21-year-old man recovering from abdominal and thoracic trauma. Nasopharyngeal (NP) swabs collected at 12 time points over a 95-day span all tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR). Genotyping revealed canonical beta-variant E484K and N501Y mutations at earlier time points. Human rhinovirus, coronavirus NL63 and respiratory syncytial virus B were detected at different time points by RT-PCR. Full blood analysis at time point 9 (day 82) showed leukopenia with lymphocytosis. The patient's NP swab tested negative for SARS-CoV-2 by RT-PCR 101 days after the first positive test. The prolonged duration of SARS-CoV-2 RNA shedding in the context of trauma presented here is unique and has important implications for COVID-19 diagnosis, management and policy guidelines

Evaluation of a commercial SARS-CoV-2 multiplex PCR genotyping assay for variant identification in resource-scarce settings

The rapid emergence and spread of numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants across the globe underscores the crucial need for continuous SARS-CoV-2 surveillance to ensure that potentially more pathogenic variants are detected early and contained. Whole genome sequencing (WGS) is currently the gold standard for COVID-19 surveillance; however, it remains cost-prohibitive and requires specialized technical skills. To increase surveillance capacity, especially in resource-scarce settings, supplementary methods that are cost- and time-effective are needed. Real-time multiplex PCR genotyping assays offer an economical and fast solution for screening circulating and emerging variants while simultaneously complementing existing WGS approaches. In this study we evaluated the AllplexTM SARS-CoV-2 Variants II multiplex real-time PCR genotyping assay, Seegene (South Korea), and implemented it in retrospectively characterizing circulating SARS-CoV-2 variants in a rural South African setting between April and October 2021, prior to the emergence of the Omicron variant in South Africa. The AllplexTM SARSCoV-2 Variants II real-time PCR assay demonstrated perfect concordance with whole-genome sequencing in detecting Beta and Delta variants and exhibited high specificity, sensitivity and reproducibility. Implementation of the assay in characterization of SARS-CoV-2 variants between April and October 2021 in a rural South African setting revealed a rapid shift from the Beta to the Delta variant between April and June. All specimens successfully genotyped in April were Beta variants and the Delta variant was not detected until May. By June, 78% of samples genotyped were Delta variants and in July >95% of all genotyped samples were Delta variants. The Delta variant continued to predominate through to the end of our analysis in October 2021. Taken together, a commercial SARS-CoV-2 variant genotyping assay detected the rapid rate at which the Delta variant displaced the Beta variant in Limpopo, an under-monitored province in South Africa. Such assays provide a quick and cost-effective method of monitoring circulating variants and should be used to complement genomic sequencing for COVID-19 surveillance especially in resource-scarce settings

Biopolymer-Based Wound Dressings with Biochemical Cues for Cell-Instructive Wound Repair

Regenerative medicine is an active research sphere that focuses on the repair, regeneration, and replacement of damaged tissues and organs. A plethora of innovative wound dressings and skin substitutes have been developed to treat cutaneous wounds and are aimed at reducing the length or need for a hospital stay. The inception of biomaterials with the ability to interact with cells and direct them toward desired lineages has brought about innovative designs in wound healing and tissue engineering. This cellular engagement is achieved by cell cues that can be biochemical or biophysical in nature. In effect, these cues seep into innate repair pathways, cause downstream cell behaviours and, ultimately, lead to advantageous healing. This review will focus on biomolecules with encoded biomimetic, instructive prompts that elicit desired cellular domino effects to achieve advanced wound repair. The wound healing dressings covered in this review are based on functionalized biopolymeric materials. While both biophysical and biochemical cues are vital for advanced wound healing applications, focus will be placed on biochemical cues and in vivo or clinical trial applications. The biochemical cues aforementioned will include peptide therapy, collagen matrices, cell-based therapy, decellularized matrices, platelet-rich plasma, and biometals

Acyldepsipeptide Analogues: A Future Generation Antibiotics for Tuberculosis Treatment

Acyldepsipeptides (ADEPs) are a new class of emerging antimicrobial peptides (AMPs), which are currently explored for treatment of pathogenic infections, including tuberculosis (TB). These cyclic hydrophobic peptides have a unique bacterial target to the conventional anti-TB drugs, and present a therapeutic window to overcome Mycobacterium Tuberculosis (M. tb) drug resistance. ADEPs exerts their antibacterial activity on M. tb strains through activation of the protein homeostatic regulatory protease, the caseinolytic protease (ClpP1P2). ClpP1P2 is normally regulated and activated by the ClpP-ATPases to degrade misfolded and toxic peptides and/or short proteins. ADEPs bind and dysregulate all the homeostatic capabilities of ClpP1P2 while inducing non-selective proteolysis. The uncontrolled proteolysis leads to M. tb cell death within the host. ADEPs analogues that have been tested possess cytotoxicity and poor pharmacokinetic and pharmacodynamic properties. However, these can be improved by drug design techniques. Moreover, the use of nanomaterial in conjunction with ADEPs would yield effective synergistic effect. This new mode of action has potential to combat and eradicate the extensive multi-drug resistance (MDR) problem that is currently faced by the public health pertaining bacterial infections, especially TB