Bacterial fitness shapes the population dynamics of antibiotic-resistant and -susceptible bacteria in a model of combined antibiotic and anti-virulence treatment

Abstract

Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body׳s natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population should be less likely to emerge. However, before the likelihood of resistance to these novel drugs emerging can be predicted, we must first establish whether such drugs can actually be effective. Many believe that anti-virulence drugs would not be powerful enough to clear existing infections, restricting their potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of antibiotic-resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention.

Against the tide: the role of bacterial adhesion in host colonization

“…If bacteria are in a planktonic state within the body, they will be removed by physical and immune clearance, unless they proliferate at a rate that exceeds the removal rate [70]. This is possible and occurs at sites that are nutrient rich, such as the intestinal lumen.…”

“…wounds) and with a well-established microbial community under the influence of host selection (e.g. intestinal tract) [70]. Thus, it is essential to collect experimental data regarding microbial behavior and host–microbe interactions at such sites, which will underpin our attempts to understand and predict the efficacy of therapies targeting infections at these sites.…”

Exploiting Interkingdom Interactions for Development of Small-Molecule Inhibitors of Candida albicans Biofilm Formation

“…As such, targeting virulence as a potential strategy for developing new antimicrobial drugs has been the focus of several research initiatives (4)(5)(6)(7)(8)(9)(10)(11). In principle, suppressing virulence behavior and locking pathogens in a vegetative non-biofilm-forming lifestyle renders them less infective and more susceptible to conventional antibiotics (4,12). While some success has been achieved against bacterial pathogens (6,10,(13)(14)(15)(16)(17)(18)(19), less focus has been placed on fungal infections, which nevertheless continue to cause serious complications and mortality in patients (8,(20)(21)(22).…”

Lokal Bakteriyel enfeksiyon durumunda çoklu antibiyotik tedavisine karşı bakteriyel direncin kesirsel mertebeden matematiksel modellemesi

“…Howeover, the most important problem derived from this therapy is the development of the bacteria resistance ability against the used antibiotic [2]. The expression of resistance to antimicrobial agents is both the logical and inevitable consequence of using these agents to treat human infections [3,4].…”