Unexpected link between an antibiotic, pannexin channels and apoptosis

Abstract

Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. In a small molecule screen, we discovered the quinolone antibiotic trovafloxacin as a novel PANX1 inhibitor. Although quinolones are widely used to treat bacterial infections, some quinolones have unexplained side effects, including deaths among children. PANX1 is a direct target of trovafloxacin at drug concentrations seen in human plasma, and its inhibition led to dysregulated fragmentation of apoptotic cells. Genetic loss of PANX1 phenocopied trovafloxacin effects, revealing a non-redundant role for pannexin channels in regulating cellular disassembly during apoptosis. Increase in drug-resistant bacteria worldwide and the dearth of new antibiotics is a major human health challenge. Comparing different quinolone antibiotics suggests that certain structural features may contribute to PANX1 blockade. These data identify a novel linkage between an antibiotic, pannexin channels, and cellular integrity, and suggest that re-engineering certain quinolones might help develop newer antibacterials.

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…92 Thus, controlling the disassembly of infected apoptotic cells may limit the spread of certain infections. 93,94 Furthermore, the protozoan Leishmania amazonesis in the 'amastigote' stage of development was shown to expose PS on its surface to enable macropinocytotic internalization by macrophages, a process that could aid infection. 95 It is worth noting that apoptotic mimicry may also be achieved by viruses through modification of the host's extracellular phospholipid code.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…In addition to their role in nucleotide release from apoptotic cells, the pannexin channels are also involved in regulating the integrity of the dying cells, 63 regulation of vascular constriction via nucleotides released by non-apoptotic mechanisms, 64 and cancer cell migration. 65 Owing to the ubiquitous expression 66 and vast regulatory mechanisms of Panx1 activation, 61,67 novel cell-type-specific knock-out and transgenic mice affecting apoptosis-specific activation may be necessary to understand its involvement during cell clearance in vivo.…”

Cell disassembly during apoptosis

“…[12] More recently, another type of less rigid and string-like apoptotic membrane protrusion, known as apoptopodia ('feet of death'), was identified on apoptotic T cells, thymocytes and fibroblasts. [13] Like microtubule spikes, the formation of apoptopodia can mediate the separation of membrane blebs. [13] Furthermore, apoptotic monocytes can generate another type of apoptotic membrane protrusion termed beaded apoptopodia that resembles 'beads-on-a-string'.…”

“…[13] Like microtubule spikes, the formation of apoptopodia can mediate the separation of membrane blebs. [13] Furthermore, apoptotic monocytes can generate another type of apoptotic membrane protrusion termed beaded apoptopodia that resembles 'beads-on-a-string'. [14] Beaded apoptopodia formation begins with the generation and elongation of an apoptopodia-like protrusion, which then becomes segmented and appears as a string of beads.…”