Fresh Approaches to Anti-Infective Therapies

Abstract

If discovery of new antibiotics continues to falter while resistance to drugs in clinical use continues to spread, society's medicine chest will soon lack effective treatments for many infections. Heritable antibiotic resistance emerges in bacteria from nonheritable resistance, also called phenotypic tolerance. This widespread phenomenon is closely linked to nonproliferative states in ways that scientists are just beginning to understand. A deeper understanding of the mechanisms of phenotypic tolerance may reveal new drug targets in the infecting organisms. At the same time, researchers must investigate ways to target the host in order to influence host-pathogen relationships. Government must reform the regulatory process for approval of new antibiotics. The private sector, government, and academia must undertake multiple, organized, multidisciplinary, parallel efforts to improve the ways in which antibiotics are discovered, tested, approved, and conserved, or it will be difficult to sustain the modern practice of medicine.

Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

“…By definition, the MIC is unaffected by the presence of class I persisters and is unchanged when persisters are isolated, expanded, and retested. Class II phenotypic tolerance is displayed by almost all of the bacteria in a population under conditions that prevent net growth during exposure to the antibiotic (7). Bacteria in the state originally called VBNC (12) are class II persisters, in that they do not replicate in some standard growth condition-in our case, solid media normally permissive to growth-and are phenotypically tolerant to diverse antibiotics (56,57).…”

“…Phenotypic tolerance to bactericidal antibiotics allows the survival of bacterial "persisters"-a population of organisms that remain viable after exposure to an antimicrobial agent at concentrations that kill the vast majority of an isogenic population at the same concentration under standard replicating conditions (7,12,55). Class I persisters are a small minority arising stochastically in a replicating bacterial population (7).…”

“…In pathologic lesions, these subpopulations can also endure exposure to chemotherapeutics, including within cavities whose bacilli populate infectious respiratory tract secretions and provide most of the material for diagnosis and treatment monitoring. When such stresses are modeled in vitro, they can lead to suppression of Mtb replication and phenotypic tolerance to antimicrobial drugs without impairing the ability of the bacteria to resume growth when the stress is relieved (7)(8)(9)(10).…”

Transforming a drug/H + antiporter into a polyamine importer by a single mutation

“…ion-coupled transporters | membrane proteins | SMR multidrug transporters | putrescine T he emergence of multiple antibiotic resistance poses a serious threat to the treatment of infectious diseases (1). Active removal of antibiotics, both drug-specific and multidrug, are important determinants of resistance (2,3).…”

Engineering Microbial Physiology with Synthetic Polymers: Cationic Polymers Induce Biofilm Formation inVibrio choleraeand Downregulate the Expression of Virulence Genes

“…In particular novel approaches that can replace or enhance current antimicrobials are highly desired. [3][4][5] Polymeric materials have often been postulated as alternatives in these areas, either as delivery vehicles for antimicrobials, 6,7 or as novel antimicrobial polymers, [8][9][10][11] and materials that can interfere with microbial adhesion. [12][13][14][15] Polymeric materials are especially attractive in these applications because of their multivalency, ease of manufacturing and the potential to precisely control polymer length and composition.…”