What are the missing pieces needed to stop antibiotic resistance?

Abstract

As recognized by several international agencies, antibiotic resistance is nowadays one of the most relevant problems for human health. While this problem was alleviated with the introduction of new antibiotics into the market in the golden age of antimicrobial discovery, nowadays few antibiotics are in the pipeline. Under these circumstances, a deep understanding on the mechanisms of emergence, evolution and transmission of antibiotic resistance, as well as on the consequences for the bacterial physiology of acquiring resistance is needed to implement novel strategies, beyond the development of new antibiotics or the restriction in the use of current ones, to more efficiently treat infections. There are still several aspects in the field of antibiotic resistance that are not fully understood. In the current article, we make a non-exhaustive critical review of some of them that we consider of special relevance, in the aim of presenting a snapshot of the studies that still need to be done to tackle antibiotic resistance.

FIGURE 1

Multiple aspects of infection and antibiotic resistance. One aspect that is not always taken in enough consideration is that the problem for human health is not antibiotic resistance; the real health problem is infection. Not just because infections have been historically a relevant cause of mortality, but also because if they are not prevented/treated, several medical procedures as surgery, transplantation or anticancer therapy would not be possible to perform. Antibiotic resistance is a problem because it impedes the use of the best anti‐infective therapies; the antibiotics, but, if infection can be prevented (i.e. through vaccination) or treated using non‐antibiotic therapies, the antibiotic resistance problem could be overcome. In this regard, it is worth mentioning that vaccination can also have a direct effect in reducing antibiotic resistance (Bloom et al., ; Jansen et al., ; Jansen & Anderson, 2018). The evolution of antibiotic resistance has to axes: selection by antibiotics themselves or by other pollutants as heavy metals or solvents (orange boxes) and transmission (blue box). Most interventions to alleviate antibiotic resistance are based in reducing selection. However, transmission is also highly relevant and sanitization, identification (and break) of transmission routes is of particular relevance. It is also worth mentioning that the problem of antibiotics resistance has been classically overcome with the development of new antibiotics. Nowadays, with few antibiotics under development, a better use of those currently available is mandatory. The development of adjuvants and of evolution‐based approaches based in identifying robust trade‐offs associated with the acquisition of resistance may help in improving the effectivity of current antibiotics (see text for more details). Green arrows indicate positive input; red lines indicate negative input.

FIGURE 2

Predicted growth rates of antibiotic‐exposed bacteria. In green, bacteriostatic antibiotic; in red, slow bactericidal; in blue, bactericidal. At the left (A) Net growth rate equals 0 (or below in the case of bactericidal antibiotics) at the MIC (all three drugs have the same MIC), but the dynamics of killing is quite different. At the right (B) sub‐MIC concentrations of the antibiotics, showing also differences in pharmacodynamics among populations with an identical MIC, so that a bacteriostatic antibiotic (green) is more bactericidal at subinhibitory concentrations than a bactericidal one (blue). This figure is modified with permission from a slide gently provided by Prof. Bruce Levin (Emory University, US).

FIGURE 3

Physiological bacterial functions involving genes that might be involved in antibiotic resistance phenotypes (intrinsic resistome). The analysis of the genes whose inactivation produces changes in bacterial susceptibility to antibiotics has shown that a large number of them do not belong to the classical categories of antibiotic resistance genes, as antibiotic inactivating enzymes or multidrug efflux pumps. Rather, as shown, they encode elements involved in regular processes of bacterial physiology (Fajardo et al., 2008).