Figure 3. Summary of Burkholderia pseudomallei resistance mechanisms compromising therapy with clinically significant antibiotics.

Enzymatic inactivation and efflux from the cell are mechanisms that compromise the use of antibiotics employed in intensive and eradication phase therapy. The CEF and AMX targets are located in the periplasm. There is experimental evidence that CEF and other β-lactams permeate the outer membrane through porins. Periplasmic β-lactams, such as AMX, are (A) inactivated by the wild-type PenA class A β-lactamase, (B) unless its activity is inhibited by CLA. Although wild-type PenA hydrolyzes CEF to some extent, it does not confer clinically significant resistance to CEF. (C) Some mutant PenA (PenA^mt) derivatives catalyze CEF hydrolysis and others (not illustrated) are refractory to CLA inhibition. Antibiotics such as DOX, TMP and TMP–SMX have cytoplasmic targets and are extruded to the extracellular milieu by the multicomponent BpeEF–OprC resistance nodulation and cell division efflux pump. As resistance nodulation and cell division pumps extrude substrates acquired from the periplasmic space, the listed antibiotics are most likely extruded either during their transit into the cell or after extrusion to the periplasm from the cytoplasmic space via an unknown mechanism.

AMX: Amoxicillin; CEF: Ceftazidime; CLA: Clavulanic acid; DOX: Doxycycline; SMX: Sulfamethoxazole; TMP: Trimethoprim.