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

Characterisation of protease resistance mutations in a South African paediatric cohort with virological failure, 2011 - 2017

Background. Advances in HIV management have improved treatment outcomes in the HIV-infected population. However, these advances have not been without multifaceted challenges. In sub-Saharan Africa, their impact is reflected in the increased emergence of HIV drug resistance mutations. With the rise in exposure of children to protease inhibitors (PIs), the possibility of increasing PI resistance remains a concern.Objectives. To describe a group of antiretroviral-experienced children with PI drug resistance mutations after failure on first- or second-line regimens in a public sector setting in South Africa.Methods. This was a retrospective cohort study of 22 children perinatally infected with HIV who had HIV genotyping conducted between January 2011 and December 2017.Results. Of the 236 children who had HIV genotyping conducted, 22 (9.3%) had evidence of HIV PI resistance mutations. Twenty-one of the 22 children (95.5%) had major mutations in the protease region of the HIV genome. Of these children, 66.7% (14/21) had loss of response to both boosted lopinavir and atazanavir, with boosted darunavir remaining susceptible in only 12 (57.1%). The most frequent major PI mutations were V82A (76.2%), M46I/M46L (76.2%), I54V (62.0%) and L76V (33.3%).Conclusions. We observed a high rate of PI resistance mutations, with a resulting loss of PIs that could be used in construction of third-line regimens. To build on improvements from the introduction of antiretroviral therapy, increased efforts are needed by both health professionals and caregivers to improve adherence measures in children perinatally infected with HIV.

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