Neutralising beta-lactamases

In the 1950s, scientists noticed that the more antibiotics from the penicillin family were used, the more beta-lactamases spread. Bacterial resistance to antibiotics was increasing. It was at this point that a real race began between the pharmaceutical industry and researchers on the one hand and bacteria on the other. The former attempted to find new molecules to fight this bacterial resistance, while the latter were continuously developing or acquiring new beta-lactamases. “New enzymes of this type result from mutations of existing beta-lactamases”, Jean-Marie Frère explains. “The strength of the bacteria is their number. Even if there’s only a chance in a billion that such a mutation will take place, the bacteria divide so quickly that this mutation ultimately occurs. If you have a chance in a billion of winning in a  lottery and you buy a billion tickets, then you really have a chance of winning!” This race led the scientific world to develop two tactics to fight this bacterial resistance. “The first one consists of disguising the penicillin so that the beta-lactamases no longer recognise the antibiotic. The beta-lactam nucleus is indeed present but hidden thanks to an envelope of substituents aimed at fooling the bacteria”, Jean-Marie Frère points out. “The second tactic aims at finding compounds capable of destroying beta-lactamases. The resulting drugs can be compared to a double-barrelled rifle: one to ‘kill’ the beta-lactamases and the other to reach the physiological target of the antibiotic, a transpeptidase that participates in the synthesis of the bacterial wall. That’s how Augmentin was discovered”, Jean-Marie Frère continues. Interestingly, most beta-lactamases and all transpeptidases have a common property: they contain an essential serine residue in their active sites.)

A very troublesome variant

Since the 1990s, a new family of beta-lactamases, first considered as a mere biochemical curiosity, has hampered research. These enzymes called metallo-beta-lactamases contain zinc (but no active site serine) and have two troublesome properties. “They escape the action of the inactivators and they gradually destroy all the antibiotics produced to fight the bacteria producing beta-lactamases”, adds Jean-Marie Frère. In 2009, the bacterium called NDM-1 (which stands for New Delhi Metallo-beta-lactamase -1) made a lot of noise after the infection of a Swedish tourist who had just made a trip to India (read: An Asian superbacterium destroys allantibiotics). “There are five varieties of this enzyme which are all as unpleasant as each other”, the professor underlines. “What makes these bacteria so dangerous is that the genetic material coding for the zinc beta-lactamase is accompanied by a whole series of genes encoding the resistance to other families of antibiotics in addition to penicillins”, he specifies. These bacteria are very difficult to eradicate. Only one or two “slightly exotic” antibiotics with serious side effects can get rid of them. Therefore, there are not many available tools to defend us against bacteria producing zinc beta-lactamases. And one “detail” further complicates matters: “Our body naturally contains a lot of zinc enzymes. Hence, it isn't easy to pinpoint the compounds that can disarm the metallo-beta-lactamases without affecting our own enzymes”, Jean-Marie Frère explains (we also contain active-site serine enzymes, but they are all very different from the bacterial beta-lactamases andtranspeptidase)