Modulating antibiotic activity towards respiratory bacterial pathogens by co-medications: a multi-target approach

• Non-antibiotic drugs show antibacterial effects alone or combined with antibiotics.
• Acting on bacteria, they modulate efflux, survival in biofilm or intracellularly.
• They may show direct antibacterial effect, synergy or antagonism with antibiotics.
• Enhancing antibiotic activity is a useful strategy to cope with resistance.
• Search of more specific and potent modulators is thus warranted.

Non-antibiotic drugs can modulate bacterial physiology and/or antibiotic activity, opening perspectives for innovative therapeutic strategies. Focusing on respiratory pathogens and considering in vitro, in vivo, and clinical data, here we examine the effect of these drugs on the expression of resistance mechanisms, biofilm formation, and intracellular survival, as well as their influence on the activity of antibiotics on bacteria. Beyond the description of the effects observed, we also comment on concentrations that are active and discuss the mechanisms of drug-drug or drug-target interactions. This discussion should be helpful in defining useful targets for adjuvant therapy and establishing the corresponding pharmacophores for further drug fine-tuning.

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